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Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR |
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| Authors: | Andrew M Petros 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 |
| Institution: | Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, United States |
| 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-xL, 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-xL mediated thrombocytopenia observed with ABT-263. |
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