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Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL
Michael F T Koehler1, Philippe Bergeron1, Edna F Choo1
1Departments of Discovery Chemistry, Drug Metabolism and Pharmacokinetics, and Early Discovery Biochemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.
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