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58 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of 5-azaindole inhibitors of O-GlcNAcase for the treatment of Alzheimer’s disease and related tauopathies Jakob Bouton , Alexis Bretteville , Gary Tresadern , Paul Shaffer , Nigel Austin , Peter Buijnsters , E. Peder Cedervall , Nicolas Darville , Ineke Fonteyn , Joseph Leenaerts , Carolina Martínez Lamenca , Liesbeth Mertens , Daniele Peeters , Adriana I. Velter , Yves Van Roosbroeck , Andreas Ebneth , Jose Manuel Bartolomé , Andrés A. Trabanco , Daniel Oehlrich Acs Medicinal Chemistry Letters 17, 1096 - 1105 DOI: 10.1021/acsmedchemlett.6c00017 Show Abstract ▼ Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.	May 2026
I03-Macromolecular Crystallography	Optimization and in vivo characterization of a series of Cbl-b inactive-state inhibitors Michael J. Lambrecht , Jun Liang , Peter Man-Un Ung , Malcolm P. Huestis , Bing-Yan Zhu , Lisa M. Barton , Georgette M. Castanedo , Jason R. Zbieg , Robin Larouche-Gauthier , Araz Jakalian , Jean-Philippe Leclerc , Arun Yadav , Pouyan Haghshenas , Samuel Aubert-Nicol , Hossein Ismaili , Liang Zhao , Mélissa Leblanc , Jian Wang , Shouliang Wang , Qiuyue Wang , Thomas Garner , Sophia Tan , Madeleine Prangley , Fabio Broccatelli , Jodie Pang , Jeremy Murray , Christine Yu , Peter Hsu , Sascha Rutz , Satoko Kakiuchi-Kiyota , Isabel Ishizuka , Dennis H. Leung , Ponien Kou , Linda Bao , Xiaojing Wang Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.6c00103 Show Abstract ▼ Abstract: Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a key negative regulator of immune function, and its inhibition is a promising strategy for cancer immunotherapy. Here, we show the optimization of a series of inactive-state Cbl-b inhibitors to improve their potency and pharmacokinetic properties. Through systematic modification of a benzylic amine and a linker region, compound 16 was identified, which demonstrates a favorable balance of biochemical potency, cellular activity, and in vitro ADME properties. Despite exhibiting high IV clearance in vivo, compound 16 achieved oral exposures sufficient to demonstrate significant tumor growth inhibition in a murine CT26 colon-cancer model.	May 2026
	Ugi-tetrazole-derived α-aminomethyl scaffolds reveal unexpected binding modes in SARS-CoV-2 3CLpro Robin Van Der Straat , Rick Oerlemans , Yingying Cong , Jeffrey Boxma , Radu G. Bulai , Clàudia Río-Bergé , Lizbe Koekemoer , Tryfon Zarganes Tzitzikas , Zhirui Guan , Peter G. Marples , Fulvio Reggiori , Matthew Groves , Alexander Dömling Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00773 Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 main protease (3CLpro) is a well-validated target for structure-guided inhibitor discovery. Here, we report α-aminomethyl tetrazole inhibitors accessed via the Ugi tetrazole multicomponent reaction (UT-4CR), enabling rapid exploration of non-classical chemical space. Initial design and modeling suggested a binding mode analogous to Ugi-derived (U-4CR) 3CLpro inhibitors, with heteroaromatic substituents engaging the S1 pocket. However, crystallographic analysis revealed an unexpected binding orientation in which the tetrazole core itself occupies the S1 pocket and forms the key interaction with His163, while the modeled substituents are solvent-exposed. This revised binding mode rationalizes the observed structure–activity relationships. Installation of an electrophilic warhead yielded covalent inhibitors with sub-micromolar enzymatic potency, and lead compound 2a displayed modest antiviral activity in infected cells. These results highlight UT-4CR-derived tetrazoles as a platform for probing the 3CLpro binding space and underscore the importance of early crystallographic validation.	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
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 small-molecule ligands for the E3 ligase STUB1/CHIP from a DNA-encoded library screen Simon C. C. Lucas , Alexander G. Milbradt , Jason Breed , Erwin De Genst , Anne Jackson , Alisa Solovyeva , Bryony Ackroyd , Matthias R. Bauer , Juntai Liu , David Longmire , Dušan Petrović , Emma L. Rivers , Christopher Stubbs , Poppy Winlow , Sana Bazzaz , Paige Dickson , Diana Gikunju , Marie-Aude Guié , John P. Guilinger , Christopher D. Hupp , Rachael Jetson , Anthony D. Keefe , Katherine Nugai , John T. S. Yeoman , Ying Zhang , Xian Feng , Dequan Yu , Christopher Phillips Acs Medicinal Chemistry Letters 16, 1445 - 1451 DOI: 10.1021/acsmedchemlett.5c00361 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.	Aug 2025
I03-Macromolecular Crystallography	Discovery of pyrimidoindolones as novel family VIII bromodomain binders Jeffrey A. Boerth , Marianne Schimpl , Simon C. C. Lucas , Jingwen Zhang , Erin L. Code , Kevin J. Embrey , Philip B. Rawlins , Haixia Wang , R. Ian Storer , Paolo Di Fruscia , Jennifer E. Nelson , Alexander G. Milbradt , Ulf Börjesson , Andrea Gohlke , Victoria Korboukh , Ariamala Gopalsamy Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.5c00120 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Suppression of oncogenic gene expression is an effective strategy for the treatment of cancer. The SWI/SNF (SWItch/Sucrose Non-Fermentable) complex plays an important role in regulating gene activation or repression, and its dysregulation has been linked to aberrant transcription activity in many types of cancer. Targeting the subunits of this complex, such as SMARCA2, SMARCA4, and PBRM1, which are part of the bromodomain family VIII, has significant therapeutic potential. Herein we report the discovery of pyrimidoindolones as a novel series of bromodomain family VIII binders identified through an NMR-based fragment screen. These binders have been optimized to achieve sub-μM affinity for the family VIII proteins SMARCA2, SMARCA4, and PRBM1, with promising physicochemical properties.	May 2025
I03-Macromolecular Crystallography	The discovery of bridged benzoazepine amides as selective allosteric modulators of RIPK1 Joanna L. Chen , Joey L. Methot , Matthew J. Mitcheltree , Andrew Musacchio , Emily B. Corcoran , Guo Feng , Alfred Lammens , Klaus Maskos , Rachel L. Palte , Meredith M. Rickard , Karin M. Otte , My S. Mansueto , Sriraman Venkat , Christopher Sondey , Maren Thomsen , Charles A. Lesburg , Xavier Fradera , Matthew J. Fell , Erin F. Dimauro , Phieng Siliphaivanh Acs Medicinal Chemistry Letters 16, 811 - 818 DOI: 10.1021/acsmedchemlett.5c00063 Show Abstract ▼ Abstract: Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.	May 2025
I04-Macromolecular Crystallography	Morita–Baylis–Hillman adduct chemistry as a tool for the design of lysine-targeted covalent ligands Marco Paolino , Giusy Tassone , Paolo Governa , Mario Saletti , Matteo Lami , Riccardo Carletti , Filippo Sacchetta , Cecilia Pozzi , Maurizio Orlandini , Fabrizio Manetti , Massimo Olivucci , Andrea Cappelli Acs Medicinal Chemistry Letters 16, 397 - 405 DOI: 10.1021/acsmedchemlett.4c00479 Diamond Proposal Number(s): [21741, 29907] Show Abstract ▼ Abstract: The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs. It is driven by two fundamental steps: (1) recognition of the target site by the molecule and (2) establishment of the covalent interaction by its reactive group. The development of new TCIs depends on the development of new warheads. Here, we propose the use of Morita–Baylis–Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as a test bench for a library of 19 MBHAs. The noncovalent interaction step was investigated by molecular docking studies, while experimentally the entire library was incubated with M2 and crystallized to confirm covalent binding with the target lysine. The results, rationalized through covalent docking analysis, support our hypothesis of MBHAs as reactive scaffolds for the design of lysine-TCIs.	Mar 2025

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