Search Results

You searched for all publications:

with publication states 'Published (Approved)'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

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	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
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Development of a series of pyrrolopyridone MAT2A inhibitors Stephen J. Atkinson , Sharan K. Bagal , Argyrides Argyrou , Sean Askin , Tony Cheung , Elisabetta Chiarparin , Muireann Coen , Iain T. Collie , Ian L. Dale , Claudia De Fusco , Keith Dillman , Laura Evans , Lyman J. Feron , Alison J. Foster , Michael Grondine , Vasudev Kantae , Gillian M. Lamont , Scott Lamont , James T. Lynch , Sten Nilsson Lill , Graeme R. Robb , Jamal Saeh , Marianne Schimpl , James S. Scott , James Smith , Bharath Srinivasan , Sharon Tentarelli , Mercedes Vazquez-Chantada , David Wagner , Jarrod J. Walsh , David Watson , Beth Williamson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c01860 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.	Mar 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	Diverse, potent, and efficacious inhibitors that target the EED subunit of the polycomb repressive complex 2 methyltransferase Sharan K. Bagal , Clare Gregson , Daniel H. O’ Donovan , Kurt G. Pike , Andrew Bloecher , Peter Barton , Alexandra Borodovsky , Erin Code , Shaun M. Fillery , Jessie Hao-Ru Hsu , Sameer P. Kawatkar , Chengzhi Li , David Longmire , Youfeng Nai , Samuel C. Nash , Andrew Pike , James Robinson , Jon A. Read , Phillip B. Rawlins , Minhui Shen , Jia Tang , Peng Wang , Haley Woods , Beth Williamson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01161 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.	Nov 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase Daniel H. O' Donovan , Clare Gregson , Martin J. Packer , Ryan Greenwood , Kurt G. Pike , Sameer Kawatkar , Andrew Bloecher , James Robinson , Jon Read , Erin Code , Jessie Hao-Ru Hsu , Minhui Shen , Haley Woods , Peter Barton , Shaun Fillery , Beth Williamson , Philip B. Rawlins , Sharan K. Bagal Bioorganic & Medicinal Chemistry Letters 39 DOI: 10.1016/j.bmcl.2021.127904 Show Abstract ▼ Abstract: Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.	May 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based design of a potent MAT2a inhibitor and in vivo evaluation in an MTAP null xenograft model Claudia De Fusco , Marianne Schimpl , Ulf Börjesson , Tony Cheung , Iain Collie , Laura Evans , Priyanka Narasimhan , Christopher Stubbs , Mercedes Vazquez-Chantada , David J. Wagner , Michael Grondine , Matthew G. Sanders , Sharon Tentarelli , Elizabeth Underwood , Argyrides Argyrou , James M. Smith , James T. Lynch , Elisabetta Chiarparin , Graeme Robb , Sharan K. Bagal , James S. Scott Journal Of Medicinal Chemistry 64, 6814 - 6826 DOI: 10.1021/acs.jmedchem.1c00067 Open Access Show Abstract ▼ Abstract: MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.	May 2021
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid identification of novel allosteric PRC2 inhibitors Jon A. Read , Jonathan Tart , Philip B. Rawlins , Clare Gregson , Karen Jones , Ning Gao , Xiahui Zhu , Ron Tomlinson , Erin Code , Tony Cheung , Huawei Chen , Sameer P. Kawatkar , Andy Bloecher , Sharan Bagal , Daniel H. O’donovan , James Robinson Acs Chemical Biology DOI: 10.1021/acschembio.9b00468 Show Abstract ▼ Abstract: Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates chromatin state and gene expression by methylating histone H3 lysine 27. EZH2 is overexpressed or mutated in various hematological malignancies and solid cancers. Our previous efforts to identify inhibitors of PRC2 methyltransferase activity by high-throughput screening (HTS) resulted in large numbers of false positives and thus a significant hit deconvolution challenge. More recently, others have reported compounds that bind to another PRC2 core subunit, EED, and allosterically inhibit EZH2 activity. This mechanism is particularly appealing as it appears to retain potency in cell lines that have acquired resistance to orthosteric EZH2 inhibition. By designing a fluorescence polarization probe based on the reported EED binding compounds, we were able to quickly and cleanly re-triage our previously challenging HTS hit list and identify novel allosteric PRC2 inhibitors.	Sep 2019
I04-Macromolecular Crystallography	Discovery of potent, selective and peripherally restricted pan-Trk kinase inhibitors for the treatment of pain Sharan K. Bagal , Mark Andrews , Bruce M. Bechle , Jianwei Bian , James Bilsland , David C. Blakemore , John F. Braganza , Peter J. Bungay , Matthew S. Corbett , Ciarán N Cronin , Jingrong Jean Cui , Rebecca Dias , Neil J. Flanagan , Samantha E. Greasley , Rachel Grimley , Kim James , Eric Johnson , Linda Kitching , Michelle L. Kraus , Indrawan Mcalpine , Asako Nagata , Sacha Ninkovic , Kiyoyuki Omoto , Stephanie Scales , Sarah E. Skerratt , Jianmin Sun , Michelle Tran-Dubé , Gareth J. Waldron , Fen Wang , Joseph S. Warmus Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00633 Show Abstract ▼ Abstract: Hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein we discuss the discovery of two potent, selective, peripherally restricted, efficacious and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.	Jun 2018

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User