Fragment-Based Discovery of Small Molecules Bound to T‑Cell Immunoglobulin and Mucin Domain-Containing Molecule 3 (TIM-3)

T-cell immunoglobulin and mucin domain-containing
molecule 3 (TIM-3;
HAVCR2) has emerged as an attractive immune checkpoint target for
cancer immunotherapy. TIM-3 is a negative regulator of the systemic
immune response to cancer and is expressed on several dysfunctional,
or exhausted, immune cell subsets. Upregulation of TIM-3 is associated
with tumor progression, poor survival rates, and acquired resistance
to antibody-based immunotherapies in the clinic. Despite the potential
advantages of small-molecule inhibitors over antibodies, the discovery
of small-molecule inhibitors has lagged behind that of antibody therapeutics.
Here, we describe the discovery of high-affinity small-molecule ligands
for TIM-3 through an NMR-based fragment screen and structure-based
lead optimization. These compounds represent useful tools to further
study the biology of TIM-3 immune modulation in cancer and serve as
a potentially useful starting point toward the discovery of TIM-3-targeted
therapeutics.