Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

Michael F T Koehler; Philippe Bergeron; Edna F Choo; Kevin Lau; Chudi Ndubaku; Danette Dudley; Paul Gibbons; Brad E Sleebs; Carl S Rye; George Nikolakopoulos; Chinh Bui; Sanji Kulasegaram; Wilhelmus J A Kersten; Brian J Smith; Peter E Czabotar; Peter M Colman; David C S Huang; Jonathan B Baell; Keith G Watson; Lisa Hasvold; Zhi-Fu Tao; Le Wang; Andrew J Souers; Steven W Elmore; John A Flygare; Wayne J Fairbrother; Guillaume Lessene

doi:10.1021/ml500030p

Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

ACS Med Chem Lett. 2014 Mar 21;5(6):662-7. doi: 10.1021/ml500030p. eCollection 2014 Jun 12.

Authors

Michael F T Koehler¹, Philippe Bergeron¹, Edna F Choo¹, Kevin Lau¹, Chudi Ndubaku¹, Danette Dudley¹, Paul Gibbons¹, Brad E Sleebs², Carl S Rye², George Nikolakopoulos², Chinh Bui², Sanji Kulasegaram², Wilhelmus J A Kersten², Brian J Smith², Peter E Czabotar², Peter M Colman², David C S Huang², Jonathan B Baell², Keith G Watson², Lisa Hasvold³, Zhi-Fu Tao³, Le Wang³, Andrew J Souers³, Steven W Elmore³, John A Flygare¹, Wayne J Fairbrother¹, Guillaume Lessene²

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.

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.