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19 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	Focused structure-based virtual screening identifies novel inhibitors of SOS1 Silvia Bonomo , Michael D. Lainchbury , Floriane Gibault , Sharan K. Bagal , J. Henry Blackwell , Jason Breed , Gavin W. Collie , Maxime Couturier , Coura Diène , Paolo Di Fruscia , Sean Gray , Craig Hughes , Dhadchayini Jeyaharan , Jason G. Kettle , Alexander G. Milbradt , Sarah Northall , Katherine Peters , Christopher J. Stubbs , Elizabeth Underwood , Yunhua Chen , Haie Hao Acs Medicinal Chemistry Letters 16 DOI: 10.1021/acsmedchemlett.5c00302 Show Abstract ▼ Abstract: SOS1 is one of the key regulators of KRAS where it catalyzes the GTP-to-GDP turnover required for KRAS activation. Inhibition of the SOS1::KRAS interaction is an attractive strategy to modulate abnormal KRAS activation, which is responsible for several malignancies. In this work, we performed a virtual screening campaign on the AstraZeneca compound collection with Heavy Atom Count between 21 and 26 and identified two novel and efficient binders of SOS1 which fulfill the minimal pharmacophoric requirements disclosed in known compounds. Subsequently, structure- and knowledge-based approaches were applied to develop these binders into functional inhibitors of SOS1.	Sep 2025
I04-Macromolecular Crystallography	Discovery of small-molecule ligands for the E3 ligase STUB1/CHIP from a DNA-encoded library screen Simon C. C. Lucas , Alexander G. Milbradt , Jason Breed , Erwin De Genst , Anne Jackson , Alisa Solovyeva , Bryony Ackroyd , Matthias R. Bauer , Juntai Liu , David Longmire , Dušan Petrović , Emma L. Rivers , Christopher Stubbs , Poppy Winlow , Sana Bazzaz , Paige Dickson , Diana Gikunju , Marie-Aude Guié , John P. Guilinger , Christopher D. Hupp , Rachael Jetson , Anthony D. Keefe , Katherine Nugai , John T. S. Yeoman , Ying Zhang , Xian Feng , Dequan Yu , Christopher Phillips Acs Medicinal Chemistry Letters 16, 1445 - 1451 DOI: 10.1021/acsmedchemlett.5c00361 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.	Aug 2025
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 a potent and orally bioavailable zwitterionic series of selective estrogen receptor degrader-antagonists James S. Scott , Darren Stead , Bernard Barlaam , Jason Breed , Rodrigo J. Carbajo , Elisabetta Chiarparin , Natalie Cureton , Paul R. J. Davey , David I. Fisher , Eric T. Gangl , Tyler Grebe , Ryan D. Greenwood , Sudhir Hande , Holia Hatoum-Mokdad , Samantha J. Hughes , Thomas A. Hunt , Tony Johnson , Stefan L. Kavanagh , Teresa C. M. Klinowska , Carrie J. B. Larner , Mandy Lawson , Andrew S. Lister , David Longmire , Stacey Marden , Thomas M. Mcguire , Caroline Mcmillan , Lindsay Mcmurray , Christopher J. Morrow , J. Willem M. Nissink , Thomas A. Moss , Daniel H. O’donovan , Radoslaw Polanski , Stephen Stokes , Kumar Thakur , Dawn Trueman , Caroline Truman , Michael J. Tucker , Haixia Wang , Nicky Whalley , Dedong Wu , Ye Wu , Bin Yang , Wenzhan Yang Journal Of Medicinal Chemistry 61 DOI: 10.1021/acs.jmedchem.2c01964 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.	Feb 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	Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist James S. Scott , Thomas A. Moss , Amber Balazs , Bernard Barlaam , Jason Breed , Rodrigo J. Carbajo , Elisabetta Chiarparin , Paul R. J. Davey , Oona Delpuech , Stephen Fawell , David I. Fisher , Sladjana Gagrica , Eric T. Gangl , Tyler Grebe , Ryan D. Greenwood , Sudhir Hande , Holia Hatoum-Mokdad , Kara Herlihy , Samantha Hughes , Thomas A. Hunt , Hoan Huynh , Sophie L. M. Janbon , Tony Johnson , Stefan Kavanagh , Teresa Klinowska , Mandy Lawson , Andrew S. Lister , Stacey Marden , Dermot F. Mcginnity , Christopher J. Morrow , J. Willem M. Nissink , Daniel H. O’donovan , Bo Peng , Radoslaw Polanski , Darren S. Stead , Stephen Stokes , Kumar Thakur , Scott R. Throner , Michael J. Tucker , Jeffrey Varnes , Haixia Wang , David M. Wilson , Dedong Wu , Ye Wu , Bin Yang , Wenzhan Yang Journal Of Medicinal Chemistry 63, 14530 - 14559 DOI: 10.1021/acs.jmedchem.0c01163 Show Abstract ▼ Abstract: Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.	Sep 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
I04-Macromolecular Crystallography	Discovery of a potent and selective oral inhibitor of ERK1/2 (AZD0364) that is efficacious in both monotherapy and combination therapy in models of non-small cell lung cancer (NSCLC) Richard A Ward , Mark J Anderton , Paul A. Bethel , Jason Breed , Calum Cook , Emma Davies , Andrew Dobson , Zhiqiang Dong , Gary Fairley , Paul Farrington , Lyman J. Feron , Vikki Flemington , Francis D Gibbons , Mark A. Graham , Ryan David Robert Greenwood , Lyndsey Hanson , Philip Hopcroft , Rachel Howells , Julian Hudson , Michael James , Clifford D. Jones , Christopher Jones , Yongchao Li , Scott Lamont , Richard James Lewis , Nicola A. Lindsay , James Francis Mccabe , Thomas M. Mcguire , Philip B. Rawlins , Karen Roberts , Linda Sandin , Iain Simpson , Steve Swallow , Jia Tang , Gary Tomkinson , Michael Tonge , Zhenhua Wang , Baochang Zhai Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01295 Diamond Proposal Number(s): [20015, 17180] Show Abstract ▼ Abstract: 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) and excellent physico-chemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging anti-tumour activity in pre-clinical models.	Nov 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Building bridges in a series of estrogen receptor degraders: an application of metathesis in medicinal chemistry James S. Scott , Jason Breed , Rodrigo J. Carbajo , Paul R. Davey , Ryan Greenwood , Hoan K. Huynh , Teresa Klinowska , Christopher J. Morrow , Thomas A. Moss , Radoslaw Polanski , J. Willem M. Nissink , Jeffrey Varnes , Bin Yang Acs Medicinal Chemistry Letters 10, 1492 - 1497 DOI: 10.1021/acsmedchemlett.9b00370 Diamond Proposal Number(s): [20015, 17180] Show Abstract ▼ Abstract: Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.	Sep 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe Nicolas Bery , Sandrine Legg , Judit Debreczeni , Jason Breed , Kevin Embrey , Christopher Stubbs , Paulina Kolasinska-Zwierz , Nathalie Barrett , Rose Marwood , Jo Watson , Jon Tart , Ross Overman , Ami Miller , Christopher Phillips , Ralph Minter , Terence H. Rabbitts Nature Communications 10, 2607 DOI: 10.1038/s41467-019-10419-2 Open Access Show Abstract ▼ Abstract: Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.	Jun 2019

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