title: Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.
abstract: The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their functional characterization as activators of apoptosis in tumor cells. Although capable of inducing cell death and preventing clonogenic survival, c-IAP-selective antagonists are significantly less potent in promoting apoptosis when compared to pan-selective compounds. However, both pan-IAP- and c-IAP-selective antagonists stimulate c-IAP1 and c-IAP2 degradation and activation of NF-kappaB pathways with comparable potencies. Therefore, although compounds that specifically target c-IAP1 and c-IAP2 are capable of inducing apoptosis, antagonism of the c-IAP proteins and XIAP is required for efficient induction of cancer cell death by IAP antagonists.
authors.affiliation: Departments of Medicinal Chemistry and Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Chudi
authors.initials: C
authors.lastname: Ndubaku
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.forename: Kevin
authors.initials: K
authors.lastname: Lau
authors.forename: Linda O
authors.initials: LO
authors.lastname: Elliott
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maurer
authors.forename: Anna V
authors.initials: AV
authors.lastname: Fedorova
authors.forename: Jasmin N
authors.initials: JN
authors.lastname: Dynek
authors.forename: Michael
authors.initials: M
authors.lastname: Koehler
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
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: Domagoj
authors.initials: D
authors.lastname: Vucic
mesh_terms: D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008545:Melanoma / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human