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.T细胞免疫球蛋白黏蛋白结构域分子3（T-cell immunoglobulin and mucin domain-containing molecule 3，TIM-3；HAVCR2）现已成为癌症免疫治疗领域极具吸引力的免疫检查点靶点。TIM-3是机体抗肿瘤系统性免疫应答的负向调控因子，可表达于多种功能失调（耗竭）的免疫细胞亚群。临床研究显示，TIM-3的上调与肿瘤进展、患者不良生存率以及抗体类免疫治疗获得性耐药显著相关。尽管小分子抑制剂相较于抗体类药物具备潜在优势，但靶向TIM-3的小分子抑制剂研发进程仍滞后于抗体治疗药物。本研究通过基于核磁共振（NMR）的片段筛选与基于结构的先导化合物优化流程，成功发现了靶向TIM-3的高亲和力小分子配体。此类化合物可作为深入研究癌症中TIM-3免疫调控生物学功能的实用工具，同时也有望成为开发靶向TIM-3治疗药物的潜在起点。