TIM-3 Inhibitor Development: Overcoming Immune Evasion in Cancer Therapy

  • J Med Chem. 2025 Dec 25;68(24):25754-25771. doi: 10.1021/acs.jmedchem.5c02693.
Lili Wang  1  2  3 ,  Hao Shen  1  2  3 ,  Binjian Jiang  1  2  3 ,  Xiao Wang  1  2  3 ,  Peng Yang  1  2  3 ,  Chengliang Sun  1  2  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41363665 DOI: 10.1021/acs.jmedchem.5c02693
Abstract

Although immune checkpoint blockade therapies targeting PD-1/PD-L1 and CTLA-4 have achieved remarkable clinical success, limitations such as low response rates and acquired resistance remain significant challenges. TIM-3 has recently emerged as a key immunosuppressive receptor and a promising therapeutic target for augmenting antitumor immunity. However, the development of TIM-3 inhibitors is highly imbalanced: multiple antibody-based candidates have entered Phase III trials, whereas small-molecule inhibitors are still in the preclinical stage, with current research remaining fragmented and lacking systematic structure-activity relationship studies. This Account systematically summarizes the structural and functional mechanisms of TIM-3, with a focus on recent advances in the discovery and development of small-molecule TIM-3 inhibitors. We highlight representative lead compounds identified through virtual screening and rational design and discuss future directions to facilitate the development of novel TIM-3-targeted agents.

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