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. 2022 Nov 24;65(22):15174-15207.
doi: 10.1021/acs.jmedchem.2c01102. Epub 2022 Nov 15.

Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432

Philip G Humphreys  1 , Niall A Anderson  1 , Paul Bamborough  1 , Andrew Baxter  1 , Chun-Wa Chung  1 , Rosa Cookson  1 , Peter D Craggs  1 , Toryn Dalton  1 , Julie C L Fournier  1 , Laurie J Gordon  1 , Heather F Gray  1 , Matthew W Gray  1 , Richard Gregory  1 , David J Hirst  1 , Craig Jamieson  2 , Katherine L Jones  1 , Hripsimee Kessedjian  1 , David Lugo  1 , Grant McGonagle  1 , Vipulkumar K Patel  1 , Christopher Patten  1 , Darren L Poole  1 , Rab K Prinjha  1 , Cesar Ramirez-Molina  1 , Inmaculada Rioja  1 , Gail Seal  1 , Kayleigh A J Stafford  1 , Rishi R Shah  1 , Daniel Tape  1 , Natalie H Theodoulou  1 , Laura Tomlinson  1 , Sabri Ukuser  1 , Ian D Wall  1 , Natalie Wellaway  1 , Gemma White  1
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Free article

Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432

Philip G Humphreys et al. J Med Chem. .
Free article

Abstract

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

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