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Identification of a small-molecule Tim-3 inhibitor to potentiate T cell–mediated antitumor immunotherapy in preclinical mouse models by Shuaiya Ma; Ye Tian; Jiali Peng; Chaojia Chen; Xueqi Peng; Fabao Zhao; Zhenyu Li; Mengzhen Li; Fangcheng Zhao; Xue Sheng; Runzhe Zong; Yiquan Li; Jiwei Zhang; Mingyan Yu; Qingfen Zhu; Xiaoyu Tian; Yuyang Li; Markus R. Neckenig; Huiqing Liu; Peng Zhan; Xuetian Yue; Zhuanchang Wu; Lifen Gao; Xiaohong Liang; Xinyong Liu; Chunyang Li; Chunhong Ma is a Medicine article available to read on EtoBox.

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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 mi

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Author

Shuaiya Ma; Ye Tian; Jiali Peng; Chaojia Chen; Xueqi Peng; Fabao Zhao; Zhenyu Li; Mengzhen Li; Fangcheng Zhao; Xue Sheng; Runzhe Zong; Yiquan Li; Jiwei Zhang; Mingyan Yu; Qingfen Zhu; Xiaoyu Tian; Yuyang Li; Markus R. Neckenig; Huiqing Liu; Peng Zhan; Xuetian Yue; Zhuanchang Wu; Lifen Gao; Xiaohong Liang; Xinyong Liu; Chunyang Li; Chunhong Ma

Publisher

American Association for the Advancement of Science (AAAS)

Published

2023

Field

Medicine (Life Sciences)