Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins

J Med Chem. 2006 Oct 19;49(21):6139-42. doi: 10.1021/jm060460o.

Abstract

A structure-based approach was employed to design a new class of small-molecule inhibitors of Bcl-2. The most potent compound 5 (TW-37) binds to Bcl-2 with a K(i) value of 290 nM and also to Bcl-xL and Mcl-1 with high affinities. Compound 5 potently inhibits cell growth in PC-3 prostate cancer cells with an IC(50) value of 200 nM and effectively induces apoptosis in a dose-dependent manner.

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

  • Apoptosis*
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Gossypol / analogs & derivatives*
  • Gossypol / chemical synthesis*
  • Gossypol / pharmacology
  • Humans
  • Models, Molecular
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / pharmacology

Substances

  • Benzamides
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfones
  • TW-37 compound
  • Gossypol