A. Gilbert

A DRUG HUNTER’S APPROACH TO MOLECULAR GLUES

Daniel S. La, Christopher G. Nasveschuk, A. Gilbert

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Abstract 2745: Identification of a selective and orally bioavailable BPTF PROTAC with anti-tumor activity in SWI/SNF mutant lung cancer

Wen Yan, Jay H. Chung, Denis E. Reyna, Dan Sherman et autres

Abstract BPTF is a bromodomain and PHD finger domain-containing protein that serves as a scaffolding subunit of the ISWI family member NURF chromatin remodeling complex. Together with interchangeable catalytic subunits SMARCA1 and SMARCA5 and additional subunits RBBP4, RBBP7, the NURF complex catalyzes …

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Applications of contemporary tools to measure plasma protein binding of targeted protein degraders

Mark Niosi, Sam Zhang, Woodrow Burchett, Carley J. S. Heck et autres

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An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes

Yuanjin Zhang, Zhonglin Liu, Marscha Hirschi, Oleg Brodsky et autres

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Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor

Christopher R. Butler, Michael Popiolek, Laura A. McAllister, Erik LaChapelle et autres

Selective activation of the M 4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can …

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Abstract LB028: Discovery and characterization of selective heterobifunctional degraders of EP300 in hematopoietic malignancies

Frederick A. Derheimer, Ninvita Givarkes, Natalie Miller, Rita Grantner et autres

Abstract The paralogous histone acetyltransferases EP300 and CREBBP are two of the master regulators of transcription by controlling both enhancer and promoter activity through histone and non-histone acetylation. EP300 and CREBBP activity is primarily driven by their acetylation of K27 and K18 …

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Expanding the ligandable proteome by paralog hopping with covalent probes

Yuanjin Zhang, Zhonglin Liu, Marsha Hirschi, Oleg Brodsky et autres

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to …

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Translational PK–PD for targeted protein degradation

Derek W. Bartlett, A. Gilbert

Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical industry. The ability to induce the degradation, and not just inhibition, of target proteins of interest (POIs) with …

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REL-1017 (Esmethadone) as Adjunctive Treatment in Patients With Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial

Maurizio Fava, Stephen M. Stahl, Luca Pani, Sara De Martin et autres

Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major …

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Intramolecular Ring-Opening Decomposition of Aryl Azetidines

Guoyun Bai, Thomas N. O’Connell, Michael A. Brodney, Christopher R. Butler et autres

The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition …

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Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes

James Schiemer, Reto Horst, Yilin Meng, Justin I. Montgomery et autres

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A kinetic proofreading model for bispecific protein degraders

Derek W. Bartlett, A. Gilbert

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