Small molecule TIM3 inhibitor for antitumor immunity

A small-molecule inhibitor of TIM3, a cell surface immune checkpoint receptor that promotes T cell exhaustion, could increase tumor killing by endogenous or CAR T cells, with more efficient tumor penetration than anti-TIM3 mAbs.

Virtual screening of a chemical library of 204,380 small molecules identified 17 compounds predicted to bind to the phosphatidyl serine binding pocket of TIM3. In vitro experiments showed a 5-(2,4-dichlorophenyl)-1-(4-methylphenyl)-3a,6a-dihydrosprio[1H-furo[3,4-c]pyrrole-3,20-(10H)-indene]-10,30,4,6(20H,3H,5H)-tetrone compound bound to human TIM3 with a K_D of 6.98 µM, and increased cytotoxic cytokine secretion without decreasing T cell viability in primary CD8⁺ T cells isolated from liver cancer patient tumors and peripheral blood, compared with vehicle. ...