ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1605741
This article is part of the Research TopicIntelligent Computing for Integrating Multi-Omics Data in Disease Diagnosis and Drug DevelopmentView all 9 articles
Structure-Based Discovery and Experimental Validation of HIT101481851 as a Potential PKMYT1 Inhibitor for Pancreatic Cancer
Provisionally accepted
- The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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PKMYT1 is a validated therapeutic target in pancreatic cancer due to its critical role in controlling the G2/M transition of the cell cycle. In this study, a structure-based drug discovery pipeline was implemented to identify novel PKMYT1 inhibitors with high binding stability and anticancer potential. Pharmacophore models were constructed from four PKMYT1 co-crystal structures, and virtual screening was performed against a large compound library. Through molecular docking and intersection analysis, five consensus high-affinity compounds were identified, among which HIT101481851 demonstrated the most favorable binding characteristics.Molecular dynamics simulations confirmed its stable interactions with key residues such as CYS-190 and PHE-240 across multiple PKMYT1 conformations. ADMET predictions indicated good gastrointestinal absorption, acceptable drug-likeness, and low risk of off-target reactivity.Furthermore, in vivo experiments showed that HIT101481851 inhibited the viability of pancreatic cancer cell lines in a dose-dependent manner while exhibiting lower toxicity toward normal pancreatic epithelial cells. These results suggest that HIT101481851 is a promising lead compound for the development of PKMYT1-targeted therapeutics in pancreatic cancer.
Keywords: PKMYT1, Pancreatic Cancer, Virtual Screening, molecular dynamics, experimental validation
Received: 03 Apr 2025; Accepted: 05 Jun 2025.
Copyright: © 2025 Wang, Wang, Yao, Zhang, Song and Ao. 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: xueren Ao, The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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