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22 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	Molecular basis of c-MET inhibition by approved small molecule drugs: a structural perspective Isabella C. Russell , Paulina Bachurska-Szpala , Lotte Van Beek , Iacovos N. Michaelides , Christopher Phillips , Arjan Snijder , Christopher J. Stubbs , Gavin W. Collie Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00713 Diamond Proposal Number(s): [20015] Open Access Show Abstract ▼ Abstract: The c-MET kinase is a driver of many cancers, and as such, there are a number of small molecule inhibitors of this kinase approved for clinical use. In this Microperspective, we provide a structural overview of the molecular basis by which these drugs inhibit c-MET, focusing on key features contributing to activity, selectivity, and drug resistance. Where necessary, relevant crystal structures not publicly available were determined and are discussed here alongside existing structural data.	Feb 2026
I04-Macromolecular Crystallography	Discovery and characterization of diverse non-nucleotide inhibitors of DNPH1 using an integrated hit finding strategy Benjamin C. Whitehurst , Niall A. Anderson , Argyrides Argyrou , Peter Astles , Bernard Barlaam , Elaine B. Cadogan , Luca Carlino , Gavin W. Collie , Alex Edwards , Linda Kitching , Yaqin Li , Alexander G. Milbradt , Jenni Nikkilä , Sarah Northall , Sara Pahlén , Saleha Patel , Wendy Savory , Markus Schade , Jonathan A. Spencer , Darren Stead , Christopher J. Stubbs , Aquan Wang , Wenxin Wang Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00651 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: DNPH1 is a hydrolase enzyme that degrades the noncanonical nucleotide 5-hydroxymethyl-2′-deoxyuridine 5′-monophosphate (hmdUMP), thus acting as a nucleotide pool sanitizer by preventing its aberrant incorporation into DNA. Recent studies have shown that loss of DNPH1 enhances the sensitivity of homologous recombination repair-deficient cancer cells to PARP inhibitors, highlighting its potential as an attractive therapeutic target. Herein we report the design and prosecution of an integrated hit finding strategy combining high-throughput screening, DNA-encoded library screening, and fragment-based lead generation which enabled the discovery of the first non-nucleotide ligands for DNPH1. We compare four hit compounds which differ markedly in their chemical structures, physicochemical properties, and binding modes and summarize parallel hit-to-lead workup efforts. We also provide discussion of the merits of an integrated approach for hit discovery when applied to challenging novel targets such as DNPH1.	Dec 2025
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	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 a series of covalent ligands that bind to Cys77 of the Von Hippel–Lindau Tumor Suppressor Protein (VHL) Simon C. C. Lucas , Yong Xu , Sarah Hewitt , Gavin W. Collie , Lucia Fusani , Ganesh Kadamur , Thomas E. Hadfield , Nancy Su , Caroline Truman , Sylvain Demanze , Haie Hao , Christopher Phillips Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.4c00582 Show Abstract ▼ Abstract: Most ligands for the Von Hippel–Lindau tumor suppressor (VHL) bind at the HIF-1α binding site. Ligands that bind to allosteric sites on VHL could be highly valuable for the field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 on VHL. Hit 2 bound selectively to Cys77 on VHL and did not alkylate the reactive Cys89 on Elongin B. It showed time- and concentration-dependent labeling, with a kinact/KI of 0.30 M–1 s–1, and does not affect binding at the HIF-1α site. This hit ligand was optimized to afford compound 15 which showed improved potency and labeling of VHL. An X-ray structure of a close analogue was determined revealing the compound binding in a shallow groove on the surface of VHL. These are the first small molecules that bind covalently to an allosteric site on VHL and provide a suitable starting point for further optimization.	Mar 2025
I24-Microfocus Macromolecular Crystallography	Specific radiation damage to halogenated inhibitors and ligands in protein–ligand crystal structures Matthew Rodrigues , Marc Cabry , Gavin Collie , Michael Carter , Craig Mcandrew , Robin L. Owen , Benjamin R. Bellenie , Yann-Vai Le Bihan , Rob L. M. Van Montfort Journal Of Applied Crystallography 57, 1951 - 1965 DOI: 10.1107/S1600576724010549 Open Access Show Abstract ▼ Abstract: Protein–inhibitor crystal structures aid medicinal chemists in efficiently improving the potency and selectivity of small-molecule inhibitors. It is estimated that a quarter of lead molecules in drug discovery projects are halogenated. Protein–inhibitor crystal structures have shed light on the role of halogen atoms in ligand binding. They form halogen bonds with protein atoms and improve shape complementarity of inhibitors with protein binding sites. However, specific radiation damage (SRD) can cause cleavage of carbon–halogen (C–X) bonds during X-ray diffraction data collection. This study shows significant C–X bond cleavage in protein–ligand structures of the therapeutic cancer targets B-cell lymphoma 6 (BCL6) and heat shock protein 72 (HSP72) complexed with halogenated ligands, which is dependent on the type of halogen and chemical structure of the ligand. The study found that metrics used to evaluate the fit of the ligand to the electron density deteriorated with increasing X-ray dose, and that SRD eliminated the anomalous signal from brominated ligands. A point of diminishing returns is identified, where collecting highly redundant data reduces the anomalous signal that may be used to identify binding sites of low-affinity ligands or for experimental phasing. Straightforward steps are proposed to mitigate the effects of C–X bond cleavage on structures of proteins bound to halogenated ligands and to improve the success of anomalous scattering experiments.	Dec 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based discovery of novel MUS81 inhibitors Gavin W. Collie , Ulf Börjesson , Yunhua Chen , Zhiqiang Dong , Paolo Di Fruscia , Andrea Gohlke , Anna Hoyle , Thomas A. Hunt , Mehul H. Jesani , Haiou Luo , Jakub Luptak , Alexander G. Milbradt , Priyanka Narasimhan , Martin Packer , Saleha Patel , Jingchuan Qiao , R. Ian Storer , Christopher J. Stubbs , Jonathan Tart , Caroline Truman , Anderson T. Wang , Matthew G. Wheeler , Jon Winter-Holt Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.3c00453 Diamond Proposal Number(s): [20015] Open Access Show Abstract ▼ Abstract: MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-μM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules.	Jun 2024
I04-Macromolecular Crystallography	Identification of novel potent NSD2-PWWP1 ligands using structure-based design and computational approaches Luca Carlino , Peter C. Astles , Bryony Ackroyd , Afshan Ahmed , Christina Chan , Gavin W. Collie , Ian L. Dale , Daniel H. O’donovan , Caroline Fawcett , Paolo Di Fruscia , Andrea Gohlke , Xiaoxiao Guo , Jessie Hao-Ru Hsu , Bethany Kaplan , Alexander G. Milbradt , Sarah Northall , Dušan Petrović , Emma L. Rivers , Elizabeth Underwood , Alice Webb Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c00215 Show Abstract ▼ Abstract: Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.	May 2024

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