JR-AB2-011

JR-AB2-011 is a selective small molecule inhibitor of the mechanistic target of rapamycin complex 2 (mTORC2). It was developed through structure-activity relationship (SAR) optimization of a hit compound (CID613034) identified in a high-throughput yeast two-hybrid screen for molecules that disrupt the protein-protein interaction between Rictor and mTOR. By specifically blocking the association of Rictor with mTOR, JR-AB2-011 prevents the assembly and kinase activity of the mTORC2 complex, leading to reduced phosphorylation of downstream substrates such as AKT (at Ser473), NDRG1, and PKCα. Notably, JR-AB2-011 does not significantly inhibit mTORC1 activity or its substrate S6K1 at effective concentrations. Preclinical studies have demonstrated its potential anti-tumor efficacy in glioblastoma, melanoma, and liposarcoma, as well as its ability to modulate macrophage polarization and provide protection in models of osteoarthritis, ulcerative colitis, and myocardial ischemia-reperfusion injury.