GDC-0152 - CAS 873652-48-3
Catalog number:
873652-48-3
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
IAP
Description:
GDC-0152 is a second mitochondrial activator of caspases (Smac) mimetic inhibitor of IAPs (Inhibitor of Apoptosis Proteins) with potential antineoplastic activity. Smac mimetic GDC-0152 binds to the Smac binding groove on IAPs, including the direct caspase inhibitor X chromosome-linked IAP (XIAP) and the cellular IAPs 1 and 2, which may inhibit their activities and promote the induction of apoptosis through apoptotic signaling pathways. IAPs are overexpressed by many cancer cell types and suppress apoptosis by binding to and inhibiting active caspases-3, -7 and -9 via their baculoviral lAP repeat (BIR) domains. Smac, the endogenous IAP antagonist, relies on its N-terminal four amino-acid motif for binding to IAPs.
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Synonyms:
GDC-0152; GDC0152; GDC 0152.
MSDS:
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Current Developer:
Genentech Inc.
1.Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152).
Flygare JA1, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG, Elliott LO, Feng B, Franklin MC, Reisner SF, Gazzard L, Halladay J, Hymowitz SG, La H, LoRusso P, Maurer B, Murray L, Plise E, Quan C, Stephan JP, Yo J Med Chem. 2012 May 10;55(9):4101-13. doi: 10.1021/jm300060k. Epub 2012 Mar 28.
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.
2.GDC-0152 induces apoptosis through down-regulation of IAPs in human leukemia cells and inhibition of PI3K/Akt signaling pathway.
Hu R1, Li J, Liu Z, Miao M, Yao K. Tumour Biol. 2015 Feb;36(2):577-84. doi: 10.1007/s13277-014-2648-8. Epub 2014 Oct 2.
The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling.
3.Evaluation of metabolism and disposition of GDC-0152 in rats using 14C labeling strategy at two different positions: a novel formation of hippuric acid from 4-phenyl-5-amino-1,2,3-thiadiazole.
Yue Q1, Mulder T, Rudewicz PJ, Solon E, Budha N, Ware JA, Lyssikatos J, Hop CE, Wong H, Khojasteh SC. Drug Metab Dispos. 2013 Feb;41(2):508-17. doi: 10.1124/dmd.112.047019. Epub 2012 Dec 4.
The compound (S)-1-[(S)-2-cyclohexyl-2-([S]-2-[methylamino]propanamido)acetyl]-N-(4-phenyl-1,2,3-thiadiazol-5-yl)pyrrolidine-2-carboxamide (GDC-0152) is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. The mass balance, pharmacokinetics, tissue distribution and metabolism of GDC-0152 was investigated in rats following intravenous administration of 15 mg/kg of [(14)C]GDC-0152, labeled either at the terminal phenyl ring (A) or at the carbonyl of the 2-amino-2-cyclohexylacetyl moiety (B). In rats, 92.2%-95.1% of the radiolabeled GDC-0152 dose was recovered. Approximately 62.3% and 25.1% of A was excreted in urine and feces, respectively. By contrast, B was excreted almost equally in urine (27.2%), feces (32.2%), and expired air (27.5%). GDC-0152 underwent extensive metabolism, with less than 9% of the dose recovered as parent in excreta. Similarly, in plasma, GDC-0152 represented 16.
4.GDC-0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway.
Yang L1, Shu T2, Liang Y3, Gu W1, Wang C1, Song X4, Fan C4, Wang W1. Int J Oncol. 2015 Apr;46(4):1651-8. doi: 10.3892/ijo.2015.2872. Epub 2015 Feb 4.
Angiopoietin-like protein 2 (ANGPTL2) plays an important role in inflammatory carcinogenesis and tumor metastasis. The compound GDC-0152 is a peptidomimetic small molecule antagonist of inhibitor of apoptosis (IAP) proteins with antitumor activity. However, the interaction between ANGPTL2 and GDC-0152 has not been studied. It has been proven that ANGPTL2 promotes metastasis of osteosarcoma. Therefore, in the present study, the effect of GDC-0152 on the malignant progression of osteosarcoma promoted by ANGPTL2 was investigated. Human osteosarcoma cell line SaOS2 cells were pre-treated or non-treated with GDC-0152 and then exposed to recombinant human ANGPTL2. The viability of SaOS2 cells was determined by MTT assay, the migration of SaOS2 cells was analyzed by chamber migration assay kit, and the SaOS2 cell apoptosis was determined by fluorescence-activated cell sorting (FACS) and nuclear staining. Treatment with ANGPTL2 increased SaOS2 cell growth and migration and decreased cell apoptosis.
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CAS 873652-48-3 GDC-0152

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