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Instruments / Technical Area	Publication Details	Published
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 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	Virtual screening in the cloud identifies potent and selective ROS1 kinase inhibitors Dušan Petrović , James S. Scott , Michael S. Bodnarchuk , Olivier Lorthioir , Scott Boyd , George M. Hughes , Jordan Lane , Allan Wu , David Hargreaves , James Robinson , Jens Sadowski Journal Of Chemical Information And Modeling DOI: 10.1021/acs.jcim.2c00644 Show Abstract ▼ Abstract: ROS1 rearrangements account for 1–2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 1015 synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 1010 subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery.	Aug 2022
I03-Macromolecular Crystallography	Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors Sébastien L. Degorce , Anna Aagaard , Rana Anjum , Iain A. Cumming , Coura R. Diène , Charlene Fallan , Tony Johnson , Karl-Johan Leuchowius , Alexandra L. Orton , Stuart Pearson , Graeme R. Robb , Alan Rosen , Graeme B. Scarfe , James S. Scott , James M. Smith , Oliver R. Steward , Ina Terstiege , Michael J. Tucker , Paul Turner , Stephen D. Wilkinson , Gail L. Wrigley , Yafeng Xue Bioorganic & Medicinal Chemistry 28 DOI: 10.1016/j.bmc.2020.115815 Show Abstract ▼ Abstract: In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.	Dec 2020
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	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
I04-1-Macromolecular Crystallography (fixed wavelength)	Tricyclic indazoles – a novel class of selective estrogen receptor degrader antagonists James S. Scott , Andrew Bailey , David Buttar , Rodrigo J. Carbajo , Jon Curwen , Paul Davey , Robert D. M. Davies , Sebastien L. Degorce , Craig Donald , Eric Gangl , Ryan David Robert Greenwood , Sam Groombridge , Tony Johnson , Scott Lamont , Mandy Lawson , Andrew Lister , Christopher Morrow , Thomas A. Moss , Jennifer H. Pink , Radoslaw Polanski Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b01837 Show Abstract ▼ Abstract: Herein we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to removal of a reactive metabolite signal in a in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl sidechain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired ERα degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.	Jan 2019
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Tetrahydroisoquinoline phenols: selective estrogen receptor downregulator antagonists with oral bioavailability in rat James S. Scott , Andrew Bailey , Robert D. M. Davies , Sébastien L. Degorce , Philip A. Macfaul , Helen Gingell , Thomas Moss , Richard A. Norman , Jennifer H. Pink , Alfred A. Rabow , Bryan Roberts , Peter D. Smith Acs Medicinal Chemistry Letters 7, 94 - 99 DOI: 10.1021/acsmedchemlett.5b00413 PMID: 26819673 Show Abstract ▼ Abstract: A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.	Jan 2016
I04-Macromolecular Crystallography	Investigation of (E)-3-[4-(2-oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic acids as oral selective estrogen receptor down-regulators Sébastien L. Degorce , Andrew Bailey , Rowena Callis , Chris De Savi , Richard Ducray , Gillian Lamont , Philip Macfaul , Mickael Maudet , Scott Martin , Rémy Morgentin , Richard A. Norman , Aurélien Peru , Jennifer H. Pink , Patrick A. Plé , Bryan Roberts , James S. Scott Journal Of Medicinal Chemistry 58 (8), 3522 - 3533 DOI: 10.1021/acs.jmedchem.5b00066 PMID: 25790336 Show Abstract ▼ Abstract: A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.	Mar 2015

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