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

  • J Med Chem. 2021 Oct 14;64(19):14757-14772. doi: 10.1021/acs.jmedchem.1c01336.
Tyson A Rietz  1 ,  Kevin B Teuscher  1 ,  Jonathan J Mills  1 ,  Rocco D Gogliotti  1 ,  Lance T Lepovitz  1 ,  W Rush Scaggs  1 ,  Keisuke Yoshida  1 ,  Kelvin Luong  2 ,  Taekyu Lee  1 ,  Stephen W Fesik  1  2  3
Affiliations
  • 1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, United States.
  • 3. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
PMID: 34597046 DOI: 10.1021/acs.jmedchem.1c01336
Abstract

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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