title: Structure-guided design of a selective BCL-X(L) inhibitor.
abstract: The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.
authors.affiliation: Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. glessene@wehi.edu.au
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.forename: Peter E
authors.initials: PE
authors.lastname: Czabotar
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.forename: Kym N
authors.initials: KN
authors.lastname: Lowes
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Adams
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Peter M
authors.initials: PM
authors.lastname: Colman
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Wilhelmus J A
authors.initials: WJ
authors.lastname: Kersten
authors.forename: Sanji
authors.initials: S
authors.lastname: Kulasegaram
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Moss
authors.forename: John P
authors.initials: JP
authors.lastname: Parisot
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Ian P
authors.initials: IP
authors.lastname: Street
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Keith G
authors.initials: KG
authors.lastname: Watson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D052160:Benzothiazoles / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006835:Hydrazones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein