title: Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity.
abstract: The prominent role of IAPs in controlling cell death and their overexpression in a variety of cancers has prompted the development of IAP antagonists as potential antitumor therapies. We describe the identification of a series of heterodimeric antagonists with highly potent antiproliferative activities in cIAP- and XIAP-dependent cell lines. Compounds 15 and 17 further demonstrate curative efficacy in human melanoma and lung cancer xenograft models and are promising candidates for advanced studies.
authors.affiliation: Bristol-Myers Squibb Research , P.O. Box 4000, Princeton, New Jersey 08543, United States.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Perez
authors.forename: Charu
authors.initials: C
authors.lastname: Chaudhry
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Emanuel
authors.forename: Caroline
authors.initials: C
authors.lastname: Fanslau
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Kyoung S
authors.initials: KS
authors.lastname: Kim
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Naglich
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Traeger
authors.forename: Ragini
authors.initials: R
authors.lastname: Vuppugalla
authors.forename: Donna D
authors.initials: DD
authors.lastname: Wei
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Randy L
authors.initials: RL
authors.lastname: Talbott
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D011392:Proline