Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)

被引：195

作者：

Flygare, John A. ^{[1
]}

Beresini, Maureen ^{[2
]}

Budha, Nageshwar ^{[3
]}

Chan, Helen ^{[4
]}

Chan, Iris T. ^{[5
]}

Cheeti, Sravanthi ^{[3
]}

Cohen, Frederick ^{[1
]}

Deshayes, Kurt ^{[6
]}

Doerner, Karl ^{[7
]}

Eckhardt, S. Gail ^{[10
]}

Elliott, Linda O. ^{[2
]}

Feng, Bainian ^{[1
]}

Franklin, Matthew C. ^{[6
]}

Reisner, Stacy Frankovitz ^{[2
]}

Gazzard, Lewis ^{[1
]}

Halladay, Jason ^{[4
]}

Hymowitz, Sarah G. ^{[8
]}

La, Hank ^{[4
]}

LoRusso, Patricia ^{[11
]}

Maurer, Brigitte ^{[8
]}

Murray, Lesley ^{[7
]}

Plise, Emile ^{[4
]}

Quan, Clifford ^{[6
]}

Stephan, Jean-Philippe ^{[2
]}

Young, Shin G. ^{[4
]}

Tom, Jeffrey ^{[6
]}

Tsui, Vickie ^{[1
]}

Um, Joanne ^{[1
]}

Varfolomeev, Eugene ^{[6
]}

Vucic, Domagoj ^{[6
]}

Wagner, Andrew J. ^{[12
]}

Wallweber, Heidi J. A. ^{[8
]}

Wang, Lan ^{[1
]}

Ware, Joseph ^{[3
]}

Wen, Zhaoyang ^{[1
]}

Wong, Harvey ^{[4
]}

Wong, Jonathan M. ^{[1
]}

Wong, Melisa ^{[1
]}

Wong, Susan ^{[4
]}

Yu, Ron ^{[9
]}

Zobel, Kerry ^{[6
]}

Fairbrother, Wayne J. ^{[6
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Clin Pharmacol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Oncol Exploratory Clin Dev, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Early Discovery Biochem, San Francisco, CA 94080 USA

[7] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[9] Genentech Inc, Dept Biostat, San Francisco, CA 94080 USA

[10] Univ Colorado Denver, Div Med Oncol, Aurora, CO 80045 USA

[11] Wayne State Univ, Dept Oncol, Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA

[12] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 09期

基金：

美国国家卫生研究院;

关键词：

NF-KAPPA-B; STRUCTURAL BASIS; MELANOMA INHIBITOR; LINKED INHIBITOR; CELL-DEATH; BIR DOMAIN; C-IAPS; ML-IAP; XIAP; CIAP1;

D O I：

10.1021/jm300060k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-l 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.

引用

页码：4101 / 4113

页数：13

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