Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin
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Chengying Xie1, Xiangling Chen1, Mingyue Zheng1, Xiaohong Liu1, Hongbin Wang1 and Liguang Lou1
1Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Liguang Lou, email: email@example.com
Keywords: BEZ235; drug resistance; mTOR; PI3K; SHR8443
Received: July 14, 2017 Accepted: October 28, 2017 Published: November 14, 2017
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in human cancer and contributes to resistance to antitumor therapy. Inhibition of key signaling proteins in this pathway therefore represents an attractive targeting strategy for cancer therapy. Here, we show that SHR8443, an imidazo [4,5-c] quinoline derivative, inhibited mammalian target of rapamycin (mTOR) kinase and PI3K, especially PI3Kα/δ/γ isoforms with picomolar potency, by binding to the ATP subunits of the respective enzymes. Inhibition of PI3K/AKT/mTOR signaling by SHR8443 induced G1 phase arrest, autophagy and apoptosis, and resulted in broad anti-proliferative activity against a panel of cancer cells with different genetic backgrounds. Furthermore, SHR8443 overcame resistance to RAF/MEK inhibitors and exhibited synergistic antitumor activity in combination with RAF/MEK inhibitors in vitro. Compared with the well-known PI3K/mTOR inhibitor BEZ235, SHR8443 showed broader and stronger efficacy against carcinoma xenografts, including those resistant to anti-HER2 antibody trastuzumab, in association with the inhibition of AKT and S6 phosphorylation in tumor tissues, and also caused no noticeable toxicity. Thus, our preclinical data show that SHR8443 is a dual PI3K/mTOR inhibitor with pharmaceutical properties favorable for use as an anticancer agent.
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