Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

  • ACS Med Chem Lett. 2014 Mar 21;5(6):662-7. doi: 10.1021/ml500030p.
Michael F T Koehler  1 ,  Philippe Bergeron  1 ,  Edna F Choo  1 ,  Kevin Lau  1 ,  Chudi Ndubaku  1 ,  Danette Dudley  1 ,  Paul Gibbons  1 ,  Brad E Sleebs  2 ,  Carl S Rye  2 ,  George Nikolakopoulos  2 ,  Chinh Bui  2 ,  Sanji Kulasegaram  2 ,  Wilhelmus J A Kersten  2 ,  Brian J Smith  2 ,  Peter E Czabotar  2 ,  Peter M Colman  2 ,  David C S Huang  2 ,  Jonathan B Baell  2 ,  Keith G Watson  2 ,  Lisa Hasvold  3 ,  Zhi-Fu Tao  3 ,  Le Wang  3 ,  Andrew J Souers  3 ,  Steven W Elmore  3 ,  John A Flygare  1 ,  Wayne J Fairbrother  1 ,  Guillaume Lessene  2
Affiliations
  • 1. Departments of Discovery Chemistry, Drug Metabolism and Pharmacokinetics, and Early Discovery Biochemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, Victoria, Australia.
  • 3. AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
PMID: 24944740 DOI: 10.1021/ml500030p
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.

Keywords
BCL-2; BCL-XL; apoptosis; cancer.
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