Identification of a small molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical models

Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC’ cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1).

ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells’ killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. Notably, ML-T7 strengthened DCs’ functions through both Tim-3 and Tim-4, consistent with the hypothesis that Tim-4 contains a similar FG-CC’ loop.