Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies.

The essential role of mTOR in promoting tumorigenesis of many cancers makes it an attractive therapeutic target. However, catalytic mTOR inhibitors, which block both mTORC1 and mTORC2, result in activation of negative feedback loops as a resistance mechanism. Selective mTORC2 inhibitors are expected to have the desired antitumor effects without engaging resistance mechanisms; however, to date, no such mTORC2 inhibitors have been developed. Using in silico screening and medicinal chemistry optimization, we identified several small molecules that bind to the unique mTORC2 component, stress-activated protein kinase-interacting protein 1 (SIN1). We demonstrate that this SIN1 inhibitor alters posttranslational modification, protein-protein interactions, and blocks mTORC2- and rapamycin-sensitive mTORC1-mediated signaling. The SIN1 inhibitor also inhibits wild-type RAS activation and downstream MAPK signaling, as well as cell proliferation of multiple cancer cell line types. SIN1 inhibition can enhance the efficacy of FDA-approved antineoplastic agents in vitro and may provide a novel approach for the treatment of different types of malignancies.