GSK1838705A

GSK1838705A is an inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor (IR; IC₅₀s = 2 and 1.6 nM, respectively).¹ It is selective for IGF-1R and IR over a panel of 47 kinases (IC₅₀s = >1,600 nM), however, it also inhibits anaplastic lymphoma kinase (ALK; IC₅₀ = 0.5 nM). GSK1838705A inhibits IGF-1 and insulin-induced phosphorylation of IGF-1R and IR in a concentration-dependent manner as well as phosphorylation of the downstream signaling markers Akt, IRS-1, and ERK in MCF-7 breast carcinoma cells. It inhibits growth in a panel of cancer cell lines (EC₅₀s = 24-8,378 nM) with the IGF-1R signaling-dependent multiple myeloma and Ewing's sarcoma cell lines being the most sensitive. In vivo, GSK1838705A completely inhibits IGF-1-induced phosphorylation of IGF-1R, Akt, and IRS-1 as well as reduces tumor growth in the COLO 205 and NIH-3T2/LISN mouse xenograft models when administered at doses of ≥1 and ≥10 mg/kg, respectively. It also induces tumor cell apoptosis and reduces tumor growth in U87MG glioma and PC3R prostate cancer mouse xenograft models.^2,3

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1. Sabbatini, P., Korenchuk, S., Rowand, J.L., et al. GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol. Cancer Ther. 8(10), 2811-2820 (2009).

2. Zhou, X., Shen, F., Ma, P., et al. GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo. Mol. Med. Rep. 12(4), 5641-5646 (2015).

3. Zhou, F., Chen, X., Fan, S., et al. GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo. Onco Targets Ther. 2015(8), 753-760 (2015).