Development of a SIN1 targeting inhibitor as a novel therapeutic approach for the treatment of malignancies.

ABSTRACT: 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 anti-tumor 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, SIN1. We demonstrate that this SIN1 inhibitor alters post-translational modification, protein-protein interactions, and blocks mTORC2- and rapamycin sensitive (RS) mTORC1-mediated signaling. The SIN1 inhibitor a

SUBMITTER: Beauchamp EM 

PROVIDER: S-EPMC12904549 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature