Development of dimeric modulators for anti-apoptotic Bcl-2 proteins

Bioorg Med Chem Lett. 2008 Jan 1;18(1):236-40. doi: 10.1016/j.bmcl.2007.10.088. Epub 2007 Oct 30.

Abstract

Bcl-2 family proteins can be classified into two subfamilies--anti-apoptotic members and pro-apoptotic members. Mechanistically, these two subfamilies can antagonize each other through heterodimerization while homodimerization has been proposed for each subfamily to carry out their corresponding anti-apoptotic or pro-apoptotic functions. To date, many small-molecule antagonists against anti-apoptotic Bcl-2 proteins have been developed, which are monomeric modulators. In this study, a series of BH3I-1 based dimeric modulators were developed with structure-activity relationship explored. Dimeric modulators compared to the monomeric antagonists have enhanced binding activity against anti-apoptotic Bcl-2 proteins. In addition, the acidic functional group was demonstrated to be critical for the binding interaction of the small-molecule antagonists with anti-apoptotic Bcl-2 proteins. Finally, the representative dimeric modulator revealed enhanced activity in inducing cytochrome c release from mitochondria compared to its monomeric counterpart. Taken together, dimerization of monomeric modulators is one practical approach to enhance the bioactivity of Bcl-2 antagonists.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Dimerization
  • Kinetics
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*
  • Thiazolidinediones
  • bcl-X Protein / antagonists & inhibitors
  • bcl-X Protein / metabolism

Substances

  • 5-(4-bromobenzylidene)-alpha-isopropyl-4-oxo-2-thioxo-3-thazolidineacetic acid
  • Proto-Oncogene Proteins c-bcl-2
  • Thiazoles
  • Thiazolidinediones
  • bcl-X Protein