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Instruments / Technical Area	Publication Details	Published
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 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
I02-Macromolecular Crystallography	Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation Jon J. G. Winter , Malcolm Anderson , Kevin Blades , Claire Brassington , Alexander L. Breeze , Christine Chresta , Kevin Embrey , Gary Fairley , Paul Faulder , M. Raymond V. Finlay , Jason G. Kettle , Thorsten Nowak , Ross Overman , S. Joe Patel , Paula Perkins , Loredana Spadola , Jonathan Tart , Julie A. Tucker , Gail Wrigley Journal Of Medicinal Chemistry 58 (5), 2265 - 2274 DOI: 10.1021/jm501660t PMID: 25695162 Open Access Show Abstract ▼ Abstract: Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.	Mar 2015

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