Delving into the Latest Updates on I-BET432 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

BET

Mechanism

BET inhibitors(Bromodomain and extra terminal domain protein inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

GSK Plc

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

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

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.

100 Deals associated with I-BET432

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