873652-48-3

Usage

Uses

Used in Pharmaceutical Industry:
GDC-0152 is used as an antitumor agent for its ability to target and inhibit IAP proteins, thereby promoting apoptosis and reducing tumor growth in cancer cells.

Biological Activity

gdc-0152 is a potent small-molecule antagonist of inhibitor of apoptosis (iap) proteins, including ml-iap, xiap, ciap1 and ciap2, that binds to the bir domain of ml-iap and the bir3 domains of xiap, ciap1 and ciap2 with values of inhibition constant ki of 14 nm, 28 nm, 17 nm and 43 nm respectively. gdc-0152 potentially inhibits tumor growth of breast cancer by promoting ciap1 degradation and inducing caspase-3/7 activation which result in the decreasing of cell viability of breast cancer cells with normal epithelial cells unaffected. in recent studies, gdc-0152 shows its ability to disrupt the binding of xiap to caspase-9 and the association of ml-iap, ciap1 and ciap2 with smac in hek293t cells.flygare ja, 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, young sg, tom j, tsui v, um j, varfolomeev e, vucic d, wagner aj, wallweber hj, wang l, ware j, wen z, wong h, wong jm, wong m, wong s, yu r, zobel k, fairbrother wj. discovery of a potent small-molecule antagonist of inhibitor of apoptosis (iap) proteins and clinical candidate for the treatment of cancer (gdc-0152). j med chem. 2012;55(9):4101-4113

Upstream product

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Relevant academic research and scientific papers

INHIBITORS OF IAP

Novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies and have the general formula I: wherein R1,R2,R3,R4,R5 and R6 are as described herein.

Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)

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 Ki 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.