Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 19, Pages 14757-14772Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01336
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Funding
- Vanderbilt University
- Biochemical and Chemical Training for Cancer Research T32 Training grant [3T32CA009582-29S1]
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TIM-3 has emerged as an attractive immune checkpoint target for cancer immunotherapy, with its upregulation associated with tumor progression and decreased survival rates. Despite the potential advantages of small-molecule inhibitors, their discovery has lagged behind that of antibody therapeutics.
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.
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