GDC-0941 as a potent PI3K inhibitor


PI3 kinases are identified as the lipid kinases, which involve in the regulation of breast tumor cell growth, migration, and survival. So far, there are a lot of PI3K isozyme-selective inhibitors that have been reported as the potential therapy drugs against tumors or other diseases, and GDC-0941 is one member of them. GDC-0941 is an orally bioavailable class I selective PI3K inhibitor, and produces the antitumor activity in human cancer cell lines in vitro and in vivo cancer models. GDC-0941 is a thieno[3,2-d]pyrimidine derivatives, and interacts with residues outside the active site of p110. [1] GDC-0941 has the solubility around 103 mg/mL in dimethyl sulfoxide (DMSO) , however it is scarcely soluble in both water and ethanol with solubility of less than 1 mg/mL. And the approximate price of GDC-0941 is $214 per 10 mg and $466 per 50 mg in, and GDC-0941 price may vary according to the proportion purity of the preparation and/or from one GDC-0941 supplier to different ones.

Kinase assays indicate that GDC-0941 show equipotent inhibitory activity against p110α and 110δ with IC50 of 3 nM, while displaying modest levels of selectivity against p110βand p110γ with IC50 of 33 nM and 75 nM, respectively. When tested against two of the p110α mutant enzymes p110α mutant E545-K and p110α mutant H1047-R detected in human cancer, GDC-0941 produces equipotent effects compared to the wild type protein. [2] The Alamar Blue assay indicates that GDC-0941 leads to inhibition of cell proliferation and signaling in human tumor cell lines including U87MG (glioblastoma), PC3 (prostate), and MDA-MB-361 (breast) cells with IC50 of  0.95 μM, 0.28 μM, and 0.72 μM, respectively. [2] Besides, GDC-0941 also produces inhibitory effect on hypoxia/anoxia-induced HIF-1α and HIF-2α expression as well as HIF activity in thyroid carcinoma cells. [3] With respect to the application in combination treatment, GDC-0941 in combination with ABT-737 display strong synergistic cytotoxicity and enhances caspase-mediated apoptosis in breast cancer cells. [4]



GDC-0941 is also selected for in vivo efficacy studies. GDC-0941 dosed orally at 75 mg/kg daily, leads to tumor growth inhibition of 83% in human U87MG glioblastoma xenografts in athymic mice. [2] Similar with in vitro results, the combination of GDC-0941 and ABT-737 also exerts increased anti-tumor efficacy on MDA-MB-231 xenograft models. Furthermore, GDC-0941 enhances the antitumor activity of docetaxel in human xenografts of breast cancer cell lines and patient-derived tumors. [5] These studies above provide the support for clinical use of GDC-0941. The studies of clinical trails about GDC-0941 has been elaborated in the previous article.

[1] Berndt A, et al. The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nature Chemical Biology. 2012, 6, 117–124.
[2] Folkes AJ, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem, 2008, 51(18), 5522-5532.
[3] Burrows N, et al. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways. J Clin Endocrinol Metab. 2011, 96(12), E1934-1943.
[4] Zheng L, et al. GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1. Cancer Lett. 2011, 309(1), 27-36.
[5] Wallin JJ, et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo Clin Cancer Res. 2012, 18(14), 3901-3911.

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