{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:18:14Z","timestamp":1781821094474,"version":"3.54.5"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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, <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fphar.2025.1605741","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T11:20:29Z","timestamp":1750245629000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Ting","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gongxiong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghui","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueren","family":"Ao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13398","DOI":"10.1038\/s41598-023-40160-2","article-title":"Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management","volume":"13","author":"Agu","year":"2023","journal-title":"Sci. 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