ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1622511
This article is part of the Research TopicNew Theories, Strategies, and Technologies for Designing Original Medicinal MoleculesView all articles
Integrated Computational and Experimental Identification of N-[(1H-1,2,4triazol-3-yl)phenyl]-1-(1H-pyrazolo[3,4-b]pyridin-3-yl)methanamide as a Potent and Selective TIM-3 Inhibitor for NSCLC Immunotherapy
Provisionally accepted
- Department of Thoracic Surgery,Affiliated Dongyang Hospital, Wenzhou Medical University, Dongyang, China
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Non-small cell lung cancer (NSCLC) remains a significant clinical challenge, necessitating exploration of novel therapeutic targets such as TIM-3. In this study, integrated computational and experimental methods were utilized to identify potent TIM-3 inhibitors. Survival analysis revealed a significant correlation between elevated TIM-3 expression and decreased patient survival. Structure-based virtual screening and molecular dynamics simulations identified HIT104310526(N-[(1H-1,2,4-triazol-3-yl)phenyl]-1-(1H-pyrazolo[3,4-b]pyridin-3yl)methanamide), a candidate exhibiting superior binding affinity and stable interactions within the TIM-3 binding pocket. MMGBSA binding free energy calculations and metadynamics further confirmed its potent binding. Physicochemical evaluations indicated favorable drug-likeness, although solubility improvement is needed. Experimental validation showed selective cytotoxicity of HIT104310526 toward NSCLC cells (A549; IC50 = 37.74 μM), with negligible toxicity to normal bronchial epithelial cells (BEAS-2). However, potential cardiotoxicity risks were identified. Collectively, HIT104310526 demonstrates substantial promise as a selective TIM-3 inhibitor, warranting further optimization for NSCLC treatment.
Keywords: TIM-3, NSCLC, HIT104310526, survival analysis, molecular dynamics, experimental validation
Received: 03 May 2025; Accepted: 29 May 2025.
Copyright: © 2025 Ying, Lou, Wu and Hu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Weiwei Hu, Department of Thoracic Surgery,Affiliated Dongyang Hospital, Wenzhou Medical University, Dongyang, China
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