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.

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