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11 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Discovery and optimization of pyrazine carboxamide AZ3246, a selective HPK1 inhibitor Jason D. Shields , David Baker , Amber Y. S. Balazs , Gayathri Bommakanti , Robert Casella , Shenggen Cao , Steve Cook , Randolph A. Escobar , Stephen Fawell , Francis D. Gibbons , Kathryn A. Giblin , Frederick W. Goldberg , Eric Gosselin , Tyler Grebe , Niresh Hariparsad , Holia Hatoum-Mokdad , Rachel Howells , Samantha J. Hughes , Anne Jackson , Iswarya Karapa Reddy , Jason G. Kettle , Gillian M. Lamont , Scott Lamont , Min Li , Sten O. Nilsson Lill , Deanna A. Mele , Anthony J. Metrano , Adelphe M. Mfuh , Lucas A. Morrill , Bo Peng , Alexander Pflug , Theresa A. Proia , Hadi Rezaei , Ryan Richards , Magdalena Richter , Kevin J. Robbins , Maryann San Martin , Marianne Schimpl , Alwin G. Schuller , Li Sha , Minhui Shen , James E. Sheppeck , Meha Singh , Stephen Stokes , Kun Song , Yuanyuan Sun , Haoran Tang , David J. Wagner , Jianyan Wang , Yanjun Wang , David M. Wilson , Allan Wu , Chengyan Wu , Dedong Wu , Ye Wu , Kevin Xu , Yue Yang , Tieguang Yao , Minwei Ye , Andrew X. Zhang , Hui Zhang , Xiang Zhai , Yanxiao Zhou , Robert E. Ziegler , Neil P. Grimster Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02631 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.	Feb 2025
I04-Macromolecular Crystallography	Highly optimized CNS penetrant inhibitors of EGFR Exon20 insertion mutations William Mccoull , Clare Thomson , Erin Braybrooke , Christina Chan , Nicola Colclough , Miguel A. Cortés González , Sabina Cosulich , Nichola L. Davies , Nicolas Floc’h , Ryan Greenwood , David Hargreaves , Peng Huang , Thomas A. Hunt , Tony Johnson , Peter Johnström , Jason G. Kettle , Mikhail Kondrashov , Demetrios H. Kostomiris , Songlei Li , Andrew Lister , Scott Martin , Darren Mckerrecher , Neville Mclean , J. Willem M. Nissink , Jonathan P. Orme , Paige Orwig , Martin J. Packer , Stuart Pearson , Lina Qin , Catarina Felisberto-Rodrigues , Adriana Savoca , Magnus Schou , Stephen Stokes , Aisha M. Swaih , Sara Talbot , Michael J. Tucker , Richard A. Ward , Emma Wadforth , Chunli Wang , Joanne Wilson , Yawen Yang Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c02811 Show Abstract ▼ Abstract: Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.	Jan 2025
I04-Macromolecular Crystallography	Design of a lead-like cysteine-targeting covalent library and the identification of hits to Cys55 of Bfl-1 Simon C. C. Lucas , Alexander G. Milbradt , J. Henry Blackwell , Silvia Bonomo , Andrew Brierley , Doyle J. Cassar , Jared Freeman , Thomas E. Hadfield , Lucas A. Morrill , Rick Riemens , Sunil Sarda , Stefan Schiesser , Daniel Wiktelius , Samiyah Ahmed , Mark J. Bostock , Ulf Börjesson , Claudia De Fusco , Carine Guerot , David Hargreaves , Sarah Hewitt , Michelle L. Lamb , Nancy Su , Ryan Whatling , Matthew Wheeler , Jason G. Kettle Journal Of Medicinal Chemistry 49 DOI: 10.1021/acs.jmedchem.4c00781 Show Abstract ▼ Abstract: Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.	Jun 2024
I04-Macromolecular Crystallography	Discovery of AZD4747, a potent and selective inhibitor of mutant GTPase KRASG12C with demonstrable CNS penetration Jason G. Kettle , Sharan K. Bagal , Derek Barratt , Michael S. Bodnarchuk , Scott Boyd , Erin Braybrooke , Jason Breed , Doyle J. Cassar , Sabina Cosulich , Michael Davies , Nichola L. Davies , Chao Deng , Andrew Eatherton , Laura Evans , Lyman J. Feron , Shaun Fillery , Emma Gleave , Frederick W. Goldberg , Miguel A. Cortés González , Carine Guerot , Afreen Haider , Stephanie Harlfinger , Rachel Howells , Anne Jackson , Peter Johnström , Paul D. Kemmitt , Alex Koers , Mikhail Kondrashov , Gillian M. Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Megan Mylrea , Samuel Nash , Michael J. Niedbala , Alison Peter , Christopher Phillips , Kurt Pike , Piotr Raubo , Graeme R. Robb , Sarah Ross , Matthew G. Sanders , Magnus Schou , Iain Simpson , Oliver Steward Journal Of Medicinal Chemistry 66, 9147 - 9160 DOI: 10.1021/acs.jmedchem.3c00746 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	Jul 2023
I04-Macromolecular Crystallography	Discovery of AZD4625, a covalent allosteric inhibitor of the mutant GTPase KRASG12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Scott Boyd , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Nichola L. Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma S. Gleave , Frederick W. Goldberg , Lyndsey Hanson , Stephanie Harlfinger , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Gillian Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Michael J. Niedbala , Christopher Phillips , Radek Polanski , Piotr Raubo , Graeme Robb , David M. Robinson , Sarah Ross , Matthew G. Sanders , Michael Tonge , Rebecca Whiteley , Stephen Wilkinson , Junsheng Yang , Wenman Zhang Journal Of Medicinal Chemistry 65, 6940 - 6952 DOI: 10.1021/acs.jmedchem.2c00369 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	May 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Alkynyl benzoxazines and dihydroquinazolines as cysteine targeting covalent warheads and their application in identification of selective irreversible kinase inhibitors Kirsten Mcaulay , Emily A. Hoyt , Morgan Thomas , Marianne Schimpl , Michael S. Bodnarchuk , Hilary J. Lewis , Derek Barratt , Deepa Bhavsar , David M. Robinson , Michael J. Deery , Derek Ogg , Gonçalo J. I. Bernardes , Richard A. Ward , Michael J. Waring , Jason G. Kettle Journal Of The American Chemical Society DOI: 10.1021/jacs.9b13391 Diamond Proposal Number(s): [12419, 20015] Show Abstract ▼ Abstract: With a resurgence in interest in covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as cysteine reactive warhead is employed to target Cys788 in c-KIT where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification whilst avoiding some of the limitations generally associated with established moieties.	May 2020
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRAS G12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma Gleave , Frederick W. Goldberg , Stephanie Harlfinger , Lyndsey Hanson , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Jennifer K. Kingston , Scott Lamont , Hilary J. Lewis , Songlei Li , Libin Liu , Derek Ogg , Christopher Phillips , Radek Polanski , Graeme Robb , David Robinson , Sarah Ross , James M. Smith , Michael Tonge , Rebecca Whiteley , Junsheng Yang , Longfei Zhang , Xiliang Zhao Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01720 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.	Feb 2020
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of N -(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H -1,2,3-triazol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors Jason G. Kettle , Rana Anjum , Evan Barry , Deepa Bhavsar , Crystal Brown , Scott Boyd , Andrew Campbell , Kristin Goldberg , Michael Grondine , Sylvie Guichard , Christopher J. Hardy , Tom Hunt , Rhys D. O. Jones , Xiuwei Li , Olga Moleva , Derek Ogg , Ross C. Overman , Martin J. Packer , Stuart Pearson , Marianne Schimpl , Wenlin Shao , Aaron Smith , James M. Smith , Darren Stead , Steve Stokes , Michael Tucker , Yang Ye Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00938 Diamond Proposal Number(s): [12419, 14631] Show Abstract ▼ Abstract: While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.	Sep 2018
I03-Macromolecular Crystallography	Potent and selective inhibitors of MTH1 probe its role in cancer cell survival Jason G. Kettle , Husam Alwan , Michal Bista , Jason Breed , Nichola L. Davies , Kay Eckersley , Shaun Fillery , Kevin M. Foote , Louise Goodwin , David R. Jones , Helena Käck , Alan Lau , J. Willem M. Nissink , Jon Read , James S. Scott , Ben Taylor , Graeme Walker , Lisa Wissler , Marta Wylot Journal Of Medicinal Chemistry 59, 2346–2361 DOI: 10.1021/acs.jmedchem.5b01760 PMID: 26878898 Open Access Show Abstract ▼ Abstract: Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the “housekeeping” enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.	Feb 2016
	Structure-based design of potent and selective inhibitors of the metabolic kinase PFKFB3 Scott Boyd , Joanna L. Brookfield , Susan E. Critchlow , Iain A. Cumming , Nicola J. Curtis , Judit Debreczeni , Sébastien L. Degorce , Craig Donald , Nicola J. Evans , Sam Groombridge , Philip Hopcroft , Neil P. Jones , Jason G. Kettle , Scott Lamont , Hilary J. Lewis , Philip Macfaull , Sheila B. Mcloughlin , Laurent J. M. Rigoreau , James M. Smith , Steve St-Gallay Journal Of Medicinal Chemistry 58 (8), 3611 - 3625 DOI: 10.1021/acs.jmedchem.5b00352 PMID: 25849762 Show Abstract ▼ Abstract: A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.	Apr 2015

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