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CIS BIOPHARMA helps cancer patients live longer and better lives. We are a biotechnology company dedicated to revolutionizing cancer treatment…
CIS BIOPHARMA helps cancer patients live longer and better lives. We are a biotechnology company dedicated to revolutionizing cancer treatment…
Liked by Richard Ward
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I am excited to be part of #ESMO24 in Barcelona to share the science behind our next-generation antibody drug conjugates (ADCs). As part of more than…
I am excited to be part of #ESMO24 in Barcelona to share the science behind our next-generation antibody drug conjugates (ADCs). As part of more than…
Liked by Richard Ward
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If you’re interested in building a career with impact, come join our Transactions team in Oncology BD at #Astrazeneca, working alongside an…
If you’re interested in building a career with impact, come join our Transactions team in Oncology BD at #Astrazeneca, working alongside an…
Liked by Richard Ward
Publications
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Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations
Journal of Medicinal Chemistry
Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging…
Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity
Other authorsSee publication -
Vinylpyridine as a Tunable Covalent Warhead Targeting C797 in EGFR
ACS Medicinal Chemistry Letters
To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine 6 as a starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12, which shows…
To further facilitate the discovery of cysteine reactive covalent inhibitors, there is a need to develop new reactive groups beyond the traditional acrylamide-type warheads. Herein we describe the design and synthesis of covalent EGFR inhibitors that use vinylpyridine as the reactive group. Structure-based design identified the quinazoline-containing vinylpyridine 6 as a starting point. Further modifications focused on reducing reactivity resulted in substituted vinyl compound 12, which shows high EGFR potency and good kinase selectivity, as well as significantly reduced reactivity compared to the starting compound 6, confirming that vinylpyridines can be applied as an alternative cysteine reactive warhead with tunable reactivity.
Other authorsSee publication -
Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release
Journal of Medicinal Chemistry
A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition–elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol…
A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition–elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU
Other authorsSee publication -
Generation of quantum configurational ensembles using approximate potentials
Journal of Chemical Theory and Computation
Conformational analysis is of paramount importance in drug design: it is crucial to determine pharmacological properties, understand molecular recognition processes, and characterize the conformations of ligands when unbound. Molecular Mechanics (MM) simulation methods, such as Monte Carlo (MC) and molecular dynamics (MD), are usually employed to generate ensembles of structures due to their ability to extensively sample the conformational space of molecules. The accuracy of these MM-based…
Conformational analysis is of paramount importance in drug design: it is crucial to determine pharmacological properties, understand molecular recognition processes, and characterize the conformations of ligands when unbound. Molecular Mechanics (MM) simulation methods, such as Monte Carlo (MC) and molecular dynamics (MD), are usually employed to generate ensembles of structures due to their ability to extensively sample the conformational space of molecules. The accuracy of these MM-based schemes strongly depends on the functional form of the force field (FF) and its parametrization, components that often hinder their performance. High-level methods, such as ab initio MD, provide reliable structural information but are still too computationally expensive to allow for extensive sampling.
Other authorsSee publication -
Potent and selective inhibitors of the epidermal growth factor receptor to overcome C797S-mediated resistance
Journal of Medicinal Chemistry
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the…
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties
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Paramol: A package for automatic parameterization of molecular mechanics force fields
Journal of Chemical Information and Modeling
The ensemble of structures generated by molecular mechanics (MM) simulations is determined by the functional form of the force field employed and its parameterization. For a given functional form, the quality of the parameterization is crucial and will determine how accurately we can compute observable properties from simulations. While accurate force field parameterizations are available for biomolecules, such as proteins or DNA, the parameterization of new molecules, such as drug candidates…
The ensemble of structures generated by molecular mechanics (MM) simulations is determined by the functional form of the force field employed and its parameterization. For a given functional form, the quality of the parameterization is crucial and will determine how accurately we can compute observable properties from simulations. While accurate force field parameterizations are available for biomolecules, such as proteins or DNA, the parameterization of new molecules, such as drug candidates, is particularly challenging as these may involve functional groups and interactions for which accurate parameters may not be available. Here, in an effort to address this problem, we present ParaMol, a Python package that has a special focus on the parameterization of bonded and nonbonded terms of druglike molecules by fitting to ab initio data.
Other authorsSee publication -
AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in KRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib
Mol Cancer Ther
The RAS-regulated RAF–MEK1/2–ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to…
The RAS-regulated RAF–MEK1/2–ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.
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Drugging the undruggable: a computational chemist's view of KRAS G12C
RSC Medicinal Chemistry
In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRASG12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a…
In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRASG12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.
Other authorsSee publication -
Preclinical comparison of the blood–brain barrier permeability of osimertinib with other EGFR TKIs
Clinical Cancer Research
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy
Other authorsSee publication -
Structural basis of the effect of activating mutations on the EGF receptor
Life Sciences Publications Ltd.
Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular…
Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA.
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Challenges and Opportunities in Cancer Drug Resistance
Chemical Reviews
There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug…
There has been huge progress in the discovery of targeted cancer therapies in recent years. However, even for the most successful and impactful cancer drugs which have been approved, both innate and acquired mechanisms of resistance are commonplace. These emerging mechanisms of resistance have been studied intensively, which has enabled drug discovery scientists to learn how it may be possible to overcome such resistance in subsequent generations of treatments. In some cases, novel drug candidates have been able to supersede previously approved agents; in other cases they have been used sequentially or in combinations with existing treatments. This review summarizes the current field in terms of the challenges and opportunities that cancer resistance presents to drug discovery scientists, with a focus on small molecule therapeutics. As part of this review, common themes and approaches have been identified which have been utilized to successfully target emerging mechanisms of resistance. This includes the increase in target potency and selectivity, alternative chemical scaffolds, change of mechanism of action (covalents, PROTACs), increases in blood–brain barrier permeability (BBBP), and the targeting of allosteric pockets. Finally, wider approaches are covered such as monoclonal antibodies (mAbs), bispecific antibodies, antibody drug conjugates (ADCs), and combination therapies.
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Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)
The Journal of Medicinal Chemistry
The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops…
The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
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Predicting protein–ligand binding affinity and correcting crystal structures with quantum mechanical calculations: lactate dehydrogenase A
Chemical Science
Accurately computing the geometry and energy of host–guest and protein–ligand interactions requires a physically accurate description of the forces in action. Quantum mechanics can provide this accuracy but the calculations can require a prohibitive quantity of computational resources. The size of the calculations can be reduced by including only the atoms of the receptor that are in close proximity to the ligand. We show that when combined with log P values for the ligand (which can be…
Accurately computing the geometry and energy of host–guest and protein–ligand interactions requires a physically accurate description of the forces in action. Quantum mechanics can provide this accuracy but the calculations can require a prohibitive quantity of computational resources. The size of the calculations can be reduced by including only the atoms of the receptor that are in close proximity to the ligand. We show that when combined with log P values for the ligand (which can be computed easily) this approach can significantly improve the agreement between computed and measured binding energies. When the approach is applied to lactate dehydrogenase A, it can make quantitative predictions about conformational, tautomeric and protonation state preferences as well as stereoselectivity and even identifies potential errors in structures deposited in the Protein Data Bank for this enzyme. By broadening the evidence base for these structures from only the diffraction data, more chemically realistic structures can be proposed.
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Kinase Drug Discovery: Modern Approaches
RSC
Kinase inhibition remains an area of significant interest, and growing importance, across academia and the pharmaceutical industry. There are now many marketed drugs that target kinases and a significant number of compounds are currently in various stages of clinical development. This book is a forward-looking analysis of a number of key areas for kinase inhibition in the coming years.
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Structure Based Design Of Covalent Inhibitors
Chemical Society Reviews
Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery…
Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach, and provide an overview of the current status of the field. We also describe some strategies and computational tools to enable successful covalent drug discovery
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Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions
Molecular Cancer Therapeutics
EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib…
EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885–96. ©2018 AACR.
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Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity
J. Chem. Inf. Model.
Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or ‘warhead’). Structural changes that increase or…
Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or ‘warhead’). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity. The half-life to adduct formation with glutathione (GSH t1/2) is a useful assay for measuring the reactivity of cysteine-targeting covalent warheads, but is limited to synthesized molecules. In this manuscript we assess the ability of several experimental and computational approaches to predict GSH t1/2 for a range of cysteine targeting warheads, including a novel method based on pKa. Furthermore, matched molecular pairs analysis has been performed against our internal compound collection, revealing structure-activity relationships between a selection of different covalent warheads. These observations and methods of prediction will be valuable in the design of new covalent inhibitors with desired levels of reactivity.
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Identification and characterisation of dual inhibitors of the USP25/28 Deubiquitinating enzyme subfamily
ACS Chem Biol
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the…
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases. The utility of these compounds as valuable probes to investigate and further explore cellular DUB biology is highlighted by the demonstration of target engagement against both USP25 and USP28 in cells. Furthermore, we demonstrate that these inhibitors are able to elicit modulation of both the total levels and the half-life of the c-Myc oncoprotein in cells, and also induce apoptosis and loss of cell viability in a range of cancer cell lines. We however observed a narrow therapeutic index compared to a panel of tissue-matched normal. Thus, it is hoped that these probes and data presented herein will further advance our understanding of the biology and tractability of DUBs as potential future therapeutic targets.
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A High-Throughput Screening Triage Workflow to Authenticate a Novel Series of PFKFB3 Inhibitors
SLAS Discovery
A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the…
A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the ratio of IC50 values at 10 times the enzyme concentration were used to identify artifact compounds. Several series of compounds were rejected as they had both high slopes and poor ratios. A small number of compounds representing the different leading series were assessed using isothermal titration calorimetry, and the X-ray crystal structure of the complex with PFKFB3 was solved. The orthogonal assay technology and isothermal calorimetry were demonstrated to be unreliable in identifying false-positive compounds in this case. Presented here is the discovery of the dihydropyrrolopyrimidinone series of compounds as active and novel inhibitors of PFKFB3, shown by X-ray crystallography to bind to the adenosine triphosphate site. The crystal structures of this series also reveal it is possible to flip the binding mode of the compounds, and the alternative orientation can be driven by a sigma-hole interaction between an aromatic chlorine atom and a backbone carbonyl oxygen. These novel inhibitors will enable studies to explore the role of PFKFB3 in driving the glycolytic phenotype of tumors.
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Inhibitors of epidermal growth factor receptor (EGFR)
Part of the series Topics in Medicinal Chemistry
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Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Weak and Promiscuous Chemical Start Point
J. Med. Chem.
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and…
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.
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Medicinal Chemistry Case History: Osimertinib (AZD9291)
Reference Module in Chemistry, Molecular Sciences and Chemical Engineering
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Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors
ACS Med. Chem. Lett.,
Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse…
Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.
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Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2
J. Med. Chem
The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent…
The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.
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The discovery and optimisation of a novel series of Dyrk1B kinase inhibitors to explore a MEK resistance hypothesis
J. Med. Chem.
Potent and selective inhibitors of Dyrk1B kinase were developed to explore the
hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells
undergoing a stress response.Other authorsSee publication -
Fragment-based Drug Discovery: Lessons and Outlook
Wiley
Contributor to chapter 17: Fragment-Based Discovery of Inhibitors of Lactate Dehydrogenase A
Other authorsSee publication -
Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
J. Med. Chem
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose…
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
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Characterisation of VPS34-IN1, a selective inhibitor of Vps34 reveals that the phosphatidylinositol 3-phosphate binding SGK3 protein kinase is a downstream target of Class III PI-3 kinase
The Biochemical Journal
The Vps34 PI3K phosphorylates phosphatidylinositol at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes. We describe a inhibitor of Vps34, termed VPS34-IN1 (25 nM IC50) that does not significantly inhibit the activity of 340 protein kinases or 25 lipid kinases tested that include all isoforms of Class I and II PI3Ks. VPS34-IN1 induces a rapid dose dependent dispersal of a specific PtdIns(3)P binding probe from endosome membranes. We explored whether SGK3…
The Vps34 PI3K phosphorylates phosphatidylinositol at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes. We describe a inhibitor of Vps34, termed VPS34-IN1 (25 nM IC50) that does not significantly inhibit the activity of 340 protein kinases or 25 lipid kinases tested that include all isoforms of Class I and II PI3Ks. VPS34-IN1 induces a rapid dose dependent dispersal of a specific PtdIns(3)P binding probe from endosome membranes. We explored whether SGK3, the only protein kinase known to interact specifically with PtdIns(3)P, might be controlled by Vps34. Mutations disrupting PtdIns(3)P-binding, ablated SGK3 kinase activity by suppressing phosphorylation of the T-loop and hydrophobic-motif residues. VPS34-IN1 induced a rapid ~55% loss of SGK3 phosphorylation. VPS34-IN1 did not inhibit activity of the SGK2 isoform that does not possess a PtdIns(3)P binding PX domain. Furthermore, Class I PI3K inhibitors that do not inhibit Vps34, suppressed SGK3 activity by ~40%. Combining VPS34-IN1 and GDC-0941 reduced SGK3 activity ~85%. This data suggests SGK3 is controlled by two pools of PtdIns(3)P. The first is produced through phosphorylation of PtdIns by Vps34. The second though the conversion of Class I PI3K product, PtdIns(3,4,5)P3 to PtdIns(3)P, via the sequential actions of the PtdIns 5-phosphatases (SHIP1/2) and PtdIns 4-phosphatase (INPP4B). VPS34-IN1 will be a useful probe to delineate physiological roles of the Vps34. Monitoring SGK3 phosphorylation and activity could be employed as a biomarker of Vps34 activity, in an analogous manner by which Akt is used to probe cellular Class I PI3K activity. Combining Class I (GDC-0941) and Class III PI3K inhibitor (VPS34-IN1) could be used as a strategy to better analyse the roles and regulation of the elusive Class II PI3K.
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Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity
Med. Chem. Commun
A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular…
A novel series of PAK1 inhibitors was discovered from a kinase directed screen. SAR exploration in the selectivity pocket and solvent tail regions was conducted to understand and optimise PAK1 potency and selectivity against targeted kinases. A liganded PAK1 crystal structure was utilised to guide compound design. Permeability and kinase selectivity impacted the translation of enzyme to cellular PAK1 potency. Compound 36 (AZ-PAK-36) demonstrated improved Gini coefficient, good PAK1 cellular potency and has utility as a tool compound for target validation studies.
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AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer
Cancer Discovery
First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This…
First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.
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Cysteine protease inhibition by nitrile-based inhibitors: a computational study
Frontiers in Chemistry
Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density…
Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism.
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Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
Journal of Medicinal Chemistry
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double…
A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
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Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation
J. Med. Chem
Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via…
Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.
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Kinase Drug Discovery
RSC Publishing
Kinase inhibition remains an area of significant interest across academia and in the pharmaceutical industry. There are now many marketed drugs which target kinases and a significant number of compounds are currently in various stages of clinical development. Although there have been a number of publications on kinase inhibition, this is the first to examine the future opportunities and challenges in targeting this important family of enzymes. The book is forward-looking and focuses on a number…
Kinase inhibition remains an area of significant interest across academia and in the pharmaceutical industry. There are now many marketed drugs which target kinases and a significant number of compounds are currently in various stages of clinical development. Although there have been a number of publications on kinase inhibition, this is the first to examine the future opportunities and challenges in targeting this important family of enzymes. The book is forward-looking and focuses on a number of key areas for kinase inhibition over the coming years.
Other authorsSee publication -
Enzymatic Characterisation of USP7 Deubiquitinating activity and Inhibition
Cell Biochem Biophys
USP7 (HAUSP) is a deubiquitinating enzyme, which plays a crucial role in regulating the levels of the p53 tumour suppressor protein, through its ability to prevent the proteasomal degradation of the Ubiquitin ligase for p53, Hdm2. Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases. In this article, we describe the…
USP7 (HAUSP) is a deubiquitinating enzyme, which plays a crucial role in regulating the levels of the p53 tumour suppressor protein, through its ability to prevent the proteasomal degradation of the Ubiquitin ligase for p53, Hdm2. Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases. In this article, we describe the characterisation of differential enzyme activity of both the full length and putative catalytic domain of human USP7 expressed in both bacterial and insect cell expression systems. We also demonstrate the way in which variations in the reducing environment surrounding the enzyme can dramatically affect both the stability of the enzyme and the range of small molecules able to inhibit the catalytic activity of the enzyme. Furthermore, we describe the validation and use of this assay for a high-throughput screening approach, again highlighting the critical nature of the enzyme's environment. Taken together, these findings not only increase our understanding of the enzymatic activity of deubiquitinating enzymes, but also highlight several key considerations of importance in the development of therapeutic agents against this novel class of therapeutic targets.
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Systematic Enumeration of Heteroaromatic Ring Systems as Reagents for Use in Medicinal Chemistry
Journal of Medicinal Chemistry
The availability of suitable chemical building blocks, or reagents, is a key factor that determines the degree of effort required to make a target molecule. If a reagent is not available and requires synthesizing, this increases the total number of synthetic steps in the route and may result in a less attractive synthetic target. This can impact most in compound collection enhancement activities or early lead identification (LI) where typically not enough information or data are available to…
The availability of suitable chemical building blocks, or reagents, is a key factor that determines the degree of effort required to make a target molecule. If a reagent is not available and requires synthesizing, this increases the total number of synthetic steps in the route and may result in a less attractive synthetic target. This can impact most in compound collection enhancement activities or early lead identification (LI) where typically not enough information or data are available to commit to such long multistep syntheses. In lead optimization (LO) projects, having access to commonly used reagents may improve the efficiency of building structure–activity relationships (SARs) and structure–property relationships (SPRs) around a core scaffold. This paper describes the systematic enumeration of key heteroaromatic reagent classes and the subsequent analysis of the availability of these in a number of commonly used databases.
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Data-mining patent literature for novel chemical reagents for use in medicinal chemistry design
MedChemComm
The properties of any molecule are fixed at the point of design. Since reliance on commercially available reagents sets to probe SAR relationships may result in incomplete interrogation of property space, efforts to pursue novel proprietary reagent collections are of clear benefit. One such approach based on fragmentation and analysis of molecules described in patent and medicinal chemistry literature is described, highlighting an example of key secondary amines with potential for broad…
The properties of any molecule are fixed at the point of design. Since reliance on commercially available reagents sets to probe SAR relationships may result in incomplete interrogation of property space, efforts to pursue novel proprietary reagent collections are of clear benefit. One such approach based on fragmentation and analysis of molecules described in patent and medicinal chemistry literature is described, highlighting an example of key secondary amines with potential for broad applicability across medicinal chemistry.
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Using protein-ligand docking to assess the chemical tractability of inhibiting a protein target
Journal of Molecular Modeling
Assessing the difficulty of inhibiting a specific protein by a small molecule can be highly valuable in risk-assessment and prioritization of a new target. In particular, when the disease linkage for a number of targets is broadly similar, being able to identify the most tractable can have a significant impact on informing target selection. With an increasing focus against new and novel protein classes, being able to assess the most likely targets to yield lead-like chemical start points can…
Assessing the difficulty of inhibiting a specific protein by a small molecule can be highly valuable in risk-assessment and prioritization of a new target. In particular, when the disease linkage for a number of targets is broadly similar, being able to identify the most tractable can have a significant impact on informing target selection. With an increasing focus against new and novel protein classes, being able to assess the most likely targets to yield lead-like chemical start points can guide the selection and the lead-generation strategy implemented. This study exploits protein-ligand docking studies on published protein x-ray crystal structures to provide guidance on the feasibility of identifying small molecule inhibitors against a range of targets.
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Toward the Comprehensive Systematic Enumeration and Synthesis of Novel Kinase Inhibitors Based on a 4-Anilinoquinazoline Binding Mode
Journal of Chemical Information and Modeling
There are currently eight small-molecule kinase inhibitors approved as cancer treatments, and a significantly larger number of compounds are in the earlier stages of clinical development. Although kinase inhibitors are most commonly developed in a cancer setting, other disease areas have been targeted. The vast majority of reported kinase small-molecule inhibitors contain functionalities that interact with the adenosine triphosphate (ATP) binding site of the kinase. The 4-anilinoquinazolines…
There are currently eight small-molecule kinase inhibitors approved as cancer treatments, and a significantly larger number of compounds are in the earlier stages of clinical development. Although kinase inhibitors are most commonly developed in a cancer setting, other disease areas have been targeted. The vast majority of reported kinase small-molecule inhibitors contain functionalities that interact with the adenosine triphosphate (ATP) binding site of the kinase. The 4-anilinoquinazolines have previously been reported as potent epidermal growth factor receptor (EGFR) inhibitors, binding at the ‘hinge’ region of the ATP site. Subsequently, this chemical series has been optimized against a number of different kinases including Src and Aurora B. Here, we detail the computational enumeration of ring systems that have the ability to make comparable interactions to the 4-anilinoquinazoline core. These were prioritized by computational, medicinal, and synthetic chemistry input, and a number of libraries were subsequently synthesized.
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Rapid Generation of a High Quality Lead for Transforming Growth Factor-β (TGF-β) Type I Receptor (ALK5)
Journal of Medicinal Chemistry
A novel class of 4-pyridinoxy-2-anilinopyridine-based TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors is reported. The binding mode of this scaffold was successfully predicted by analyzing possible docked binding modes of literature inhibitors and novel synthetic ideas. Compounds such as 19 are potent ALK5 inhibitors with good physicochemical and pharmacokinetic properties and thus represent high quality leads for further optimization.
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Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations
The Biochemical Journal
Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action…
Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whereas mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whereas mutation of either Gly796 or Cys797 resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors, but occurred with varying frequencies. Importantly, the presence of C797S with T790M in the same EGFR allele conferred complete resistance to erlotinib, lapatinib and CI-1033. The combination of erlotinib and CI-1033 effectively reduced the number of drug-resistant clones, suggesting a possible clinical strategy to overcome drug resistance. Interestingly, our results also indicate that co-expression of ErbB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has an impact upon the EGFR resistance mutations obtained, suggesting that ErbB2 may play an active role in the acquisition of drug-resistant mutations.
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Structure-based virtual screening for low molecular weight chemical starting points for dipeptidyl peptidase IV inhibitors
Journal of Medicinal Chemistry
Structure-based virtual screening was performed against the target dipeptidyl peptidase IV (DPP-IV) to identify good chemical starting points for medicinal chemistry. A database of available compounds was filtered by calculated physical properties and undesired chemistry. This database was matched against two in-house designed DPP-IV pharmacophores, and the hits from these pharmacophore searches were docked into a DPP-IV crystal structure. Compounds were then selected for testing and 51 active…
Structure-based virtual screening was performed against the target dipeptidyl peptidase IV (DPP-IV) to identify good chemical starting points for medicinal chemistry. A database of available compounds was filtered by calculated physical properties and undesired chemistry. This database was matched against two in-house designed DPP-IV pharmacophores, and the hits from these pharmacophore searches were docked into a DPP-IV crystal structure. Compounds were then selected for testing and 51 active compounds were identified from a list of 4000 compounds tested. These had activities ranging from 30% to 82% when tested at a concentration of 30 μM in an enzyme inhibition assay.
Honors & Awards
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ACS Heroes Of Chemistry 2018
American Chemical Society
Heroes of Chemistry is an annual award sponsored by the American Chemical Society that recognizes talented industrial chemical scientists whose work has led to the development of successful commercialized products ingrained with chemistry for the benefit of humankind
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Capps Green Zomoya Award 2018
Royal Society Of Chemistry
The Capps Green Zomaya Award recognises work in medicinal or computational medicinal chemistry -
Malcolm Campbell Memorial Award
Royal Society of Chemistry Biological and Medicinal Chemistry Sector
http://www.rsc.org/Membership/Networking/InterestGroups/BMCS/Activities/CampbellAward.asp
Malcolm Campbell Award Announcement – Osimertinib Team
The Royal Society of Chemistry Biological and Medicinal Chemistry Sector is proud to announce the winners of the Malcolm Campbell Memorial Prize for 2017.
The prize has been awarded to Sam Butterworth, Darren Cross, Ray Finlay, Richard A. Ward and Michael J. Waring for contributions to the team that discovered TAGRISSO(TM)…http://www.rsc.org/Membership/Networking/InterestGroups/BMCS/Activities/CampbellAward.asp
Malcolm Campbell Award Announcement – Osimertinib Team
The Royal Society of Chemistry Biological and Medicinal Chemistry Sector is proud to announce the winners of the Malcolm Campbell Memorial Prize for 2017.
The prize has been awarded to Sam Butterworth, Darren Cross, Ray Finlay, Richard A. Ward and Michael J. Waring for contributions to the team that discovered TAGRISSO(TM) (osimertinib, AZD9291) at AstraZeneca.
Osimertinib, a potent, oral, CNS-active, irreversible epidermal growth factor receptor (EGFR) inhibitor that was developed specifically for the treatment of patients with T790M mutation positive NSCLC, has demonstrated significant clinically meaningful improvement in efficacy compared to standard of care chemotherapy in these patients, with fewer serious adverse events. In record time, just 2 years and 9 months after the first patient was dosed, osimertinib was provisionally approved for patients whose tumours have a specific epidermal growth factor receptor (EGFR) mutation (T790M) and whose disease has progressed due to resistance to other EGFR-blocking therapy.
The BMCS Committee wishes to express its gratitude for the high-quality entries from both academia and industry for the 2017 award.
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