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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Use of direct-to-biology strategies for the discovery of 2′-deoxynucleoside 5′-monophosphate N-glycosidase (DNPH1) PROTACs Niall A. Anderson , Bernard Barlaam , Argyrides Argyrou , Peter C. Astles , Hanna Bruss , Elaine B. Cadogan , Luca Carlino , Luz Alonso-Crisostomo , Gavin W. Collie , Alex J. Edwards , Anastasiia Gryniukova , James Hall , Kunzah Jamal , Joshua Kent , Linda Kitching , Christopher Kourra , Carolyn Lam , Alexander G. Milbradt , Jenni Nikkilä , Sarah Northall , Mark J. O’connor , Jeroen Overman , Claudio Pathe , Wendy Savory , Daniel Slade , Jonathan A. Spencer , Darren Stead , Christopher J. Stubbs , Benjamin C. Whitehurst , Sabrina Winfield Journal Of Medical Chemistry 68 DOI: 10.1021/acs.jmedchem.5c02337 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: 2′-Deoxynucleoside 5′-monophosphate N-glycosidase (DNPH1) has emerged as an attractive target for cancer therapeutics exploiting DNA damage response pathways, yet chemical degraders for interrogating DNPH1 biology are lacking. We report the accelerated discovery of potent DNPH1 PROTACs using a direct-to-biology synthesis and screening platform. We employed miniaturized, array-based chemistry to generate a broad library of quinazoline-based PROTACs capable of recruiting a variety of different E3 ligases. Screening crude reaction mixtures in a cellular degradation assay enabled rapid identification of multiple nanomolar DNPH1 PROTACs, exemplified by compound 59, which achieved near-complete DNPH1 degradation and demonstrated strong functional activity in BRCA1 mutant cell lines. Mechanistic studies confirmed selective, proteasome- and VHL-dependent protein knockdown and recapitulation of phenotypic outcomes observed with DNPH1 genetic loss, including sensitization to hmdU treatment. Our findings highlight the power of D2B methodology to streamline PROTAC development and establish quinazoline-based degraders as robust chemical tools to advance DNPH1-targeted cancer research.	Nov 2025
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery and optimization of a non-nucleoside-based series of inhibitors of 2′-deoxynucleoside 5′-monophosphate glycosidase (DNPH1) Bernard Barlaam , Luz Alonso-Crisostomo , Niall A. Anderson , Argyrides Argyrou , Peter C. Astles , Elaine B. Cadogan , Luca Carlino , Gavin W. Collie , Nichola L. Davies , James Hall , Linda Kitching , Xianxi Li , Filippos Michopoulos , Alexander G. Milbradt , Jenni Nikkilä , Sarah Northall , Mark J. O'Connor , Xiaohiu Pei , Joseph Shaw , Danial Slade , Harriet Southgate , Darren Stead , Christopher J. Stubbs , Benjamin C. Whitehurst , Bin Xing , Yihao Yuan , Jie Zhou Journal Of Medical Chemistry DOI: 10.1021/acs.jmedchem.5c02356 Show Abstract ▼ Abstract: DNPH1 is a nucleotide pool sanitizer that cleaves 5-hydroxymethyl-2-deoxyuridine-5-monophosphate (hmdUMP), preventing incorporation of the correspondent non-natural nucleotide into DNA. Recent findings have demonstrated that loss of DNPH1 could potentiate the sensitivity of PARP inhibitors in homologous recombination repair (HRR)-deficient cancers. We report the optimization of a non-nucleoside-based series of DNPH1 inhibitors. Starting from a weak compound 1 (binding affinity pIC50 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC50 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC50 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.	Nov 2025
I04-Macromolecular Crystallography	Discovery of AZD8421: A potent CDK2 inhibitor with selectivity against other CDK family members and the human kinome Avipsa Ghosh , Afshan Ahmed , Konstantina Amoiradaki , Amber Y. S. Balazs , Bernard Barlaam , Michael S. Bodnarchuk , Gavin W. Collie , Ian L. Dale , Christopher R. Denz , Lisa Drew , Scott D. Edmondson , Jun Fan , Stephen Fawell , Frederick W. Goldberg , Ariamala Gopalsamy , Michael Grondine , Grace Guo , Sudhir M. Hande , Holia Hatoum-Mokdad , Alexander W. Hird , Rachel Howells , Jessie Hao-Ru Hsu , Jessica Hudson , Anne Jackson , Michelle L. Lamb , Gillian M. Lamont , Scott Lamont , Phillip A. Lichtor , Lisa Mcwilliams , David Milne , Scott N. Mlynarski , Priyanka Narasimhan , Matthew F. Peters , Alexander Pflug , Hannah Kate Pollard , Meile Qin , Corinne Reimer , Kevin J. Robbins , James Robinson , Li Sha , Hongyao She , James E. Sheppeck , Baljinder Singh , Kun Song , Qibin Su , Reem Telmesani , Scott Throner , Christina Vasalou , Lei Wang , Yanjun Wang , David M. Wilson , Poppy Winlow , Wenzhan Yang , Tieguang Yao , Yun Zhang , Zirong Zhang , Diana Zindel , Jeffrey W. Johannes Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c01478 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity. To this end, we report the discovery of AZD8421, a potent and highly selective CDK2 inhibitor, which exhibits superior selectivity for CDK2 over CDK1, other CDK family members, and the broader human kinome. AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent.	Sep 2025
I04-Macromolecular Crystallography	Discovery and in vivo efficacy of AZ-PRMT5i-1, a novel PRMT5 inhibitor with high MTA cooperativity James M. Smith , Bernard Barlaam , David Beattie , Lauren Bradshaw , Ho Man Chan , Elisabetta Chiarparin , Olga Collingwood , Sophie L. Cooke , Anna Cronin , Iain Cumming , Emma Dean , Judit É. Debreczeni , Iván Del Barco Barrantes , Coura Diene , Davide Gianni , Carine Guerot , Xiaoxiao Guo , Sinem Guven , Thomas G. Hayhow , Ted Hong , Paul D. Kemmitt , Gillian M. Lamont , Scott Lamont , James T. Lynch , Lisa Mcwilliams , Shaun Moore , Piotr Raubo , Graeme R. Robb , James Robinson , James S. Scott , Bharath Srinivasan , Oliver Steward , Christopher J. Stubbs , Karl Syson , Lixiang Tan , Oliver Turner , Elizabeth Underwood , Jelena Urosevic , Mercedes Vazquez-Chantada , Amy L. Whittaker , David M. Wilson , Jon J. Winter-Holt Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c00097 Show Abstract ▼ Abstract: PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel “MTA-cooperative” compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 (“AZ-PRMT5i-1”), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.	Jul 2024
I04-Macromolecular Crystallography	Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors Neil P. Grimster , Lakshmaiah Gingipalli , Amber Balazs , Bernard Barlaam , Scott Boiko , Scott Boyd , Hannah Dry , Frederick W. Goldberg , Tim Ikeda , Tony Johnson , Sameer Kawatkar , Paul Kemmitt , Scott Lamont , Olivier Lorthioir , Adelphe Mfuh , Joe Patel , Andy Pike , Jon Read , Romulo Romero , Ujjal Sarkar , Li Sha , Iain Simpson , Kun Song , Qibin Su , Haixia Wang , David Watson , Allan Wu , Troy E. Zehnder , Xiaolan Zheng , Shaolu Li , Zhiqiang Dong , Dejian Yang , Yanwei Song , Peng Wang , Xuemei Liu , James E. Dowling , Scott D. Edmondson Bioorganic & Medicinal Chemistry Letters 91 DOI: 10.1016/j.bmcl.2023.129352 Show Abstract ▼ Abstract: Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.	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
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

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