CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation

  • J Med Chem. 2022 Apr 14;65(7):5660-5674. doi: 10.1021/acs.jmedchem.1c02168.
Kendall Carrasco  1 ,  Camille Montersino  1  2 ,  Carine Derviaux  1  2 ,  Magali Saez-Ayala  1 ,  Laurent Hoffer  1 ,  Audrey Restouin  1  2 ,  Rémy Castellano  1  2 ,  Justine Casassa  1 ,  Philippe Roche  1 ,  Eddy Pasquier  1 ,  Sébastien Combes  1 ,  Xavier Morelli  1  2 ,  Yves Collette  1  2 ,  Stéphane Betzi  1
Affiliations
  • 1. CNRS, INSERM, Aix-Marseille Univ, Institut Paoli-Calmettes, CRCM, Marseille 13009, France.
  • 2. Institut Paoli-Calmettes, Plateforms HiTS & TrGET, Marseille 13009, France.
PMID: 35348328 DOI: 10.1021/acs.jmedchem.1c02168
Abstract

Differentially screening the Fr-PPIChem chemical library on the bromodomain and extra-terminal (BET) BRD4-BDII versus -BDI bromodomains led to the discovery of a BDII-selective tetrahydropyridothienopyrimidinone (THPTP)-based compound. Structure-activity relationship (SAR) and hit-to-lead approaches allowed us to develop CRCM5484, a potent inhibitor of BET proteins with a preferential and 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI). Its very low activity was demonstrated in various cell-based assays, corresponding with recent data describing other selective BDII compounds. However, screening on a drug sensitivity and resistance-profiling platform revealed its ability to modulate the anti-leukemic activity in combination with various FDA-approved and/or in-development drugs in a cell- and context-dependent differential manner. Altogether, the results confirm the originality of the THPTP molecular mode of action in the bromodomain (BD) cavity and its potential as a starting scaffold for the development of potent and selective bromodomain inhibitors.