Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders

J Med Chem. 2020 Apr 23;63(8):4047-4068. doi: 10.1021/acs.jmedchem.9b02076. Epub 2020 Apr 10.

Abstract

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / administration & dosage*
  • Benzimidazoles / chemistry*
  • Cell Line, Tumor
  • Drug Delivery Systems / methods*
  • Drug Discovery / methods*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-6 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Xenograft Model Antitumor Assays / methods

Substances

  • BCL6 protein, human
  • Benzimidazoles
  • Proto-Oncogene Proteins c-bcl-6
  • benzimidazolone