2. Academic Validation
  3. Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate

Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate

  • J Med Chem. 2022 Feb 10;65(3):2262-2287. doi: 10.1021/acs.jmedchem.1c01747.
Philip G Humphreys 1,  Stephen J Atkinson 1,  Paul Bamborough 1,  Rino A Bit 1,  Chun-Wa Chung 1,  Peter D Craggs 1,  Leanne Cutler 1,  Rob Davis 1,  Alan Ferrie 1,  GangLi Gong 2,  Laurie J Gordon 1,  Matthew Gray 1,  Lee A Harrison 1,  Thomas G Hayhow 1,  Andrea Haynes 1,  Nick Henley 1,  David J Hirst 1,  Ian D Holyer 1,  Matthew J Lindon 1,  Cerys Lovatt 1,  David Lugo 1,  Scott McCleary 1,  Judit Molnar 1,  Qendresa Osmani 1,  Chris Patten 1,  Alex Preston 1,  Inmaculada Rioja 1,  Jonathan T Seal 1,  Nicholas Smithers 1,  Fenglai Sun 2,  Dalin Tang 2,  Simon Taylor 1,  Natalie H Theodoulou 1 3,  Clare Thomas 1,  Robert J Watson 1,  Christopher R Wellaway 1,  Linrong Zhu 2,  Nicholas C O Tomkinson 3,  Rab K Prinjha 1
Affiliations

Affiliations

  • 1 GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
  • 2 WuXi Shanghai STA Pharmaceutical R&D Co., Ltd., No. 90 Delin Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
  • 3 WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
PMID: 34995458 DOI: 10.1021/acs.jmedchem.1c01747
Abstract

Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.

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