BC-LI-0186 (4-(2,3-dimethyl-5-oxo-4-propan-2-ylpyrazol-1-yl)-N-(2-phenoxyethyl)benzenesulfonamide) is a potent and selective inhibitor of the interaction of Leucyl-tRNA synthetase (LRS) and Ras-related GTP-binding protein D (RagD) with IC50 of 46.11 nM. BC-LI-0186 competitively binds the RagD interaction site of LRS with Kd of 42.1 nM and has no effect on LRS-vps34, LRS-eprs, RagB-RagD association, mTORC1 complex formation. BC-LI-0186 potently inhibits the activity of tumor-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. BC-LI-0186 can be used for lung cancer-related research.

LeuRS-RagD:42.1 nM(Kd), LeuRS-RagD:46.11 nM

Administration of 0-20 μM BC-LI-0186 followed by starved for 90?min in the leucine-free medium and then in the serum-free media for 15?min inhibits phosphorylation of S6K dose- and time-dependently, but it has no effects on phosphorylation of AKT (S473)[1]. Administration of 0-20 μM BC-LI-0186 for 6 hours induces cleaved poly ADP-ribose polymerase (PARP) and caspase-3 and an increase of p62 in A549 and H460 cells[1]. In NSCLC cells, BC-LI-0186 exhibits cytotoxic effect at nanomolar concentration, it exhibits IC50 values of 98 nM, 206 nM, 55 nM, 78 nM, 83 nM, 86 nM, 102 nM, 109 nM, 128 nM, and 206 nM in A549, H460, H2228, H1703, SNU1330, H1650, H2009, H358, H2279, H460, and H596 cells, respectively[1].BC-LI-0186 overcomes acquired rapamycin resistance and inhibits the mTORC1 pathway in isogenic HCT116 cell lines that harbored either M TOR WT (HCT116 MW) or S2035I mutations (HCT116 MM), it exhibits little changed efficacy between the wild-type and mutant cells (GI50:39.49 ?nM and 42.03?nM, EC50:105.03 nM and 100.45 ?nM)[1].

Intraperitoneal injection of 50?mg/kg BC-LI-0186 alone or combines with cisplatin alone for 2 weeks(bid for 5?days per week) exhibits antitumor effects and significantly reduces tumor size compared with treatment with vehicle in an LSL K-ras G12D lung cancer animal model[1].