Discovery of Small-Molecule TIM-3 Inhibitors for Acute Myeloid Leukemia Using Pharmacophore-Based Virtual Screening

T-cell immunoglobulin and mucin domain 3 (TIM-3) is anegativeimmune checkpoint that represents a promising target for cancer immunotherapy.Although encouraging results have been observed for TIM-3 inhibitionin the context of acute myeloid leukemia (AML), targeting TIM-3 iscurrently restricted to monoclonal antibodies (mAbs). To fill thisgap, we implemented a pharmacophore-based screening approach to identifysmall-molecule TIM-3 inhibitors. Our approach resulted in the identificationof hit compounds with TIM-3 binding affinity. Subsequently, we usedthe structure-activity relationship (SAR) by a catalog approachto identify compound A-41 with submicromolar TIM-3 bindingaffinity. Remarkably, A-41 demonstrated the ability toblock TIM-3 interactions with key ligands and inhibited the immunosuppressivefunction of TIM-3 using an in vitro coculture assay.This work will pave the way for future drug discovery efforts aimingat the development of small-molecule inhibitors TIM-3 for AML.