1. Academic Validation
  2. Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787

Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787

  • J Med Chem. 2024 Jun 27;67(12):10464-10489. doi: 10.1021/acs.jmedchem.4c00959.
David J Hirst 1 Paul Bamborough 1 Niam Al-Mahdi 1 Davina C Angell 1 Heather A Barnett 1 Andrew Baxter 1 Rino A Bit 1 Jack A Brown 1 Chun-Wa Chung 1 Peter D Craggs 1 Robert P Davis 1 Emmanuel H Demont 1 Alan Ferrie 1 Laurie J Gordon 1 Isobel Harada 1 Tim C T Ho 1 Ian D Holyer 1 Edward Hooper-Greenhill 1 Katherine L Jones 1 Matthew J Lindon 1 Cerys Lovatt 1 David Lugo 1 Claire Maller 1 Grant McGonagle 1 Cassie Messenger 1 Darren J Mitchell 1 David D Pascoe 1 Vipulkumar K Patel 1 Christopher Patten 1 Darren L Poole 1 Rishi R Shah 1 Inmaculada Rioja 1 Kayleigh A J Stafford 1 Daniel Tape 1 Simon Taylor 1 Natalie H Theodoulou 1 Laura Tomlinson 1 Ian D Wall 1 Christopher R Wellaway 1 Gemma White 1 Rab K Prinjha 1 Philip G Humphreys 1
Affiliations

Affiliation

  • 1 GSK Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.
Abstract

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.

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