Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR

  • Bioorg Med Chem Lett. 2010 Nov 15;20(22):6587-91. doi: 10.1016/j.bmcl.2010.09.033.
Andrew M Petros  1 ,  Jeffrey R Huth ,  Thorsten Oost ,  Cheol-Min Park ,  Hong Ding ,  Xilu Wang ,  Haichao Zhang ,  Paul Nimmer ,  Renaldo Mendoza ,  Chaohong Sun ,  Jamey Mack ,  Karl Walter ,  Sarah Dorwin ,  Emily Gramling ,  Uri Ladror ,  Saul H Rosenberg ,  Steven W Elmore ,  Stephen W Fesik ,  Philip J Hajduk
Affiliations
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, United States.
PMID: 20870405 DOI: 10.1016/j.bmcl.2010.09.033
Abstract

The Bcl-2 Family of proteins plays a major role in the regulation of Apoptosis, or programmed cell death. Overexpression of the anti-apoptotic members of this family (Bcl-2, Bcl-x(L), and Mcl-1) can render Cancer cells resistant to chemotherapeutic agents and therefore these proteins are important targets for the development of new anti-cancer agents. Here we describe the discovery of a potent, highly selective, Bcl-2 Inhibitor using SAR by NMR and structure-based drug design which could serve as a starting point for the development of a Bcl-2 selective anti-cancer agent. Such an agent would potentially overcome the Bcl-x(L) mediated thrombocytopenia observed with ABT-263.

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