2. Academic Validation
  3. Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models

Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models

  • Sci Transl Med. 2023 Nov 15;15(722):eadg6752. doi: 10.1126/scitranslmed.adg6752.
Shuaiya Ma 1,  Ye Tian 1 2,  Jiali Peng 1,  Chaojia Chen 1,  Xueqi Peng 1,  Fabao Zhao 2,  Zhenyu Li 3,  Mengzhen Li 1,  Fangcheng Zhao 1,  Xue Sheng 1,  Runzhe Zong 4,  Yiquan Li 4,  Jiwei Zhang 2,  Mingyan Yu 5,  Qingfen Zhu 5,  Xiaoyu Tian 6,  Yuyang Li 6,  Markus R Neckenig 2,  Huiqing Liu 4,  Peng Zhan 2,  Xuetian Yue 4,  Zhuanchang Wu 1,  Lifen Gao 1,  Xiaohong Liang 1,  Xinyong Liu 2,  Chunyang Li 7,  Chunhong Ma 1
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
  • 3 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China.
  • 4 School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P. R. China.
  • 5 Shandong Institute for Food and Drug Control, Jinan, Shandong 250101, P. R. China.
  • 6 Center for Cell Structure and Function, Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, P. R. China.
  • 7 Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
PMID: 37967204 DOI: 10.1126/scitranslmed.adg6752
Abstract

T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of TIM-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of TIM-3. ML-T7 strengthened DCs' functions through both TIM-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the TIM-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and TIM-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking TIM-3 and warrants further study.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163028
    99.85%, Tim-3抑制剂
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