title: Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152).
abstract: A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. jflygare@gene.com
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Maureen
authors.initials: M
authors.lastname: Beresini
authors.forename: Nageshwar
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authors.lastname: Budha
authors.forename: Helen
authors.initials: H
authors.lastname: Chan
authors.forename: Iris T
authors.initials: IT
authors.lastname: Chan
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Cheeti
authors.forename: Frederick
authors.initials: F
authors.lastname: Cohen
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Karl
authors.initials: K
authors.lastname: Doerner
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Linda O
authors.initials: LO
authors.lastname: Elliott
authors.forename: Bainian
authors.initials: B
authors.lastname: Feng
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Franklin
authors.forename: Stacy Frankovitz
authors.initials: SF
authors.lastname: Reisner
authors.forename: Lewis
authors.initials: L
authors.lastname: Gazzard
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maurer
authors.forename: Lesley
authors.initials: L
authors.lastname: Murray
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.forename: Clifford
authors.initials: C
authors.lastname: Quan
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Shin G
authors.initials: SG
authors.lastname: Young
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Tom
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Joanne
authors.initials: J
authors.lastname: Um
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Heidi J A
authors.initials: HJ
authors.lastname: Wallweber
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Joseph
authors.initials: J
authors.lastname: Ware
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Wen
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wong
authors.forename: Melisa
authors.initials: M
authors.lastname: Wong
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D013830:Thiadiazoles; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020169:Caspases