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
  • 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.

Products