2. Academic Validation
  3. Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

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

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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