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26 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	Discovery of CNS penetrant SOS1 inhibitors for the treatment of KRAS-dependent cancers Sharan K. Bagal , Coura R. N. Diène , Sandra Stefanovic-Barrett , Jason Breed , Gregory W. Kauffman , Michael S. Bodnarchuk , Gavin W. Collie , Anna D. Staniszewska , Abhishek Srivastava , Elsa Irving , Doyle J. Cassar , Sean Gray , Craig Hughes , Jason G. Kettle , Samuel Nash , Sarah Northall , Alison Peter , Markus Schade , Christopher J. Stubbs , Aaron Smith , Lucy Young Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c03800 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kpu,u. Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRASG12C inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRASG12C inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.	Jun 2026
I04-Macromolecular Crystallography	Targeting the interaction of NRF2 and β-TrCP with molecular glues Daniel H. O Donovan , Jon Winter-Holt , Gavin W. Collie , Maria E. Cuomo , David J. Mcgarry , Millie Fox , Bo Kyung Alex Seong , Ursula Grazini , Peter Barton , David Longmire , Andrew Lister , Yong Xu , Hazel Mak , Evelyne J. Barrey , Marta Acebrón-García-De-Eulate , Magdalena Richter , Nisha Peter , Maxime Couturier , Gustavo J. Gutierrez , Ryan Guilbert , Wankyu Lee , Pamela A. Lochhead , Argyrides Argyrou Acs Chemical Biology DOI: 10.1021/acschembio.5c01006 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Inhibiting the oncogenic driver NRF2 in non-small cell lung cancer (NSCLC) represents a promising yet challenging clinical opportunity. Small molecules that enhance the NRF2:β-TrCP interaction (“molecular glues”) could hold therapeutic potential by promoting the ubiquitination and proteasomal degradation of NRF2. NRX-252114 is a molecular glue previously reported to promote the interaction between β-catenin and β-TrCP. We now find that NRX-252114 can also enhance the association between β-TrCP and NRF2 phosphodegron peptides. To leverage this novel interaction for the development of NRF2:β-TrCP molecular glues, we synthesized and evaluated a library of chemical analogues, guided by homology modeling and subsequently by X-ray crystallography. Surprisingly, structural elucidation of the NRF2:β-TrCP complex revealed occlusion of the presumed molecular glue binding pocket. This mechanistic insight explains the limited affinity enhancement for analogues of NRX-252114, and provides a structural rationale for the lack of NRF2 degradation in cells. Our findings broaden the scope of β-TrCP-targeted molecular glues, demonstrate that NRF2 is “glueable” at the peptide level, and provide mechanistic guidance for future efforts to target the pharmacologically elusive NRF2 pathway in cancer.	Mar 2026
I04-Macromolecular Crystallography	A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader Monica C. Rodrigo-Brenni , Jasper C. Komen , Ghaith M. Hamza , Natacha Bohin , Tomas Adomavicius , Angelo Andres , Stefan Blaho , Ulf Börjesson , Gavin W. Collie , Gian Marco De Donatis , Frederik Eisele , Ning Gao , Andrea Gohlke , Christoph Grebner , Frida Gustafsson , Andreas Hock , Cecilia Kankkonen , Praveen Kumar , Emilyanne Leonard , Xin Li , Ruth Macdonald , Katja Madeyski-Bengtson , Eric Miele , Philip Nevin , Jeroen Overman , Fiona Pachl , Claudio Pathe , Matthew W. D. Perry , Christopher Phillips , Andy Pike , Ian Purvis , Timothy Rasmusson , Sophie Regan , Linda Reilly , Jonathan Rose , R. Ian Storer , Jingwen Wang , Xiang Zhai , Iacovos N. Michaelides , Kevin Moreau Nature Communications 38 DOI: 10.1038/s41467-026-70663-1 Open Access Show Abstract ▼ Abstract: Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). When these IMiD scaffolds are integrated into proteolysis targeting chimeras (PROTACs), they can inadvertently lead to the degradation of these neosubstrates alongside the intended protein of interest (POI), raising safety concerns. This study profiles existing PROTACs and reveals instances of undesired degradation of IMiD-associated neosubstrates. We have developed in vitro hematopoietic assays to scrutinize the IMiD effects and describe the mechanistic insights on cell differentiation rewiring towards megakaryocytes together with an activation of the interferon response that is phenocopied by an Ikaros knock-out model. Moreover, we have identified a CRBN ligand that mitigates these safety liabilities and can be effectively incorporated into PROTACs. This advancement provides a promising path toward safer preclinical development of PROTACs, especially as the field expands into chronic disease treatments beyond oncology.	Mar 2026
I04-Macromolecular Crystallography	Structural studies of βTrCP reveal plasticity in binding modes of consensus and nonconsensus degrons Gavin W. Collie , Hazel Mak , Marta Acebron-Garcia-De-Eulate , Argyrides Argyrou , Maxime Couturier , Maria Emanuela Cuomo , Daniel H. O Donovan , Isabella C. Russell , Geoffrey Wells , Jon Winter-Holt Acs Chemical Biology DOI: 10.1021/acschembio.5c01007 Diamond Proposal Number(s): [20015] Open Access Show Abstract ▼ Abstract: The E3 ligase βTrCP regulates a significant number of important cytosolic proteins by recognizing and binding to a “DSGXXS” consensus phosphodegron sequence, resulting in the ubiquitination and degradation of target proteins. While many of the substrates of βTrCP have strong disease links, there is high-resolution structural data available for just one of these proteins in complex with βTrCP. Here, we describe the development of a robust crystallographic system for βTrCP and report high-resolution crystal structures for βTrCP in complex with degrons from five new targets, encompassing the important cancer proteins, WEE1, claspin, ATF4, PDCD4, and IκBα. Interestingly, these structures reveal the molecular basis by which βTrCP can recognize and bind both consensus and nonconsensus degron peptides and reveal an overall general plasticity in degron binding mode. We also provide a biochemical assessment of the binding affinities of these peptides for βTrCP, adding further insight into the molecular interactions observed in the crystal structures. Finally, computational analyses of the βTrCP complexes identify opportunities for potential molecular glue approaches.	Mar 2026
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
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	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
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

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