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

Autor: Rietz TA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Teuscher KB; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Mills JJ; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Gogliotti RD; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Lepovitz LT; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Scaggs WR; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Yoshida K; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Luong K; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, United States., Lee T; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States., Fesik SW; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Oct 14; Vol. 64 (19), pp. 14757-14772. Date of Electronic Publication: 2021 Oct 01.
DOI: 10.1021/acs.jmedchem.1c01336
Abstrakt: 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.
Databáze: MEDLINE
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