Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

J Med Chem. 2018 Jul 26;61(14):6110-6120. doi: 10.1021/acs.jmedchem.8b00483. Epub 2018 Jul 17.

Abstract

We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with Ki values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Biological Availability
  • Cell Cycle Proteins
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Proteins
  • Transcription Factors
  • bromodomain and extra-terminal domain protein, human