title: Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
abstract: A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hasvold
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Erwin R
authors.initials: ER
authors.lastname: Boghaert
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Catron
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Colman
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kovar
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia ; Department of Pharmacology and Therapeutics, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitten
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Chudi O
authors.initials: CO
authors.lastname: Ndubaku
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Nimmer
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Anatol
authors.initials: A
authors.lastname: Oleksijew
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Phillips
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Morey L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville, VIC 3052, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, VIC 3010, Australia.
authors.forename: Keith G
authors.initials: KG
authors.lastname: Watson
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: John
authors.initials: J
authors.lastname: Xue
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080 United States.
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Tse
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.affiliation: AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064 United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
keywords: BCL-2; BCL-XL; apoptosis; cancer