Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer
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 potenti...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1605741/full |
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| _version_ | 1849422240413646848 |
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| author | Ting Wang Ting Wang Jingyu Wang Gongxiong Yao Hongchao Zhang Chenghui Song Xueren Ao |
| author_facet | Ting Wang Ting Wang Jingyu Wang Gongxiong Yao Hongchao Zhang Chenghui Song Xueren Ao |
| author_sort | Ting Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9d534cd83bf74d61bddf61ef8dc4dcef |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-9d534cd83bf74d61bddf61ef8dc4dcef2025-08-20T03:31:11ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-06-011610.3389/fphar.2025.16057411605741Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancerTing Wang0Ting Wang1Jingyu Wang2Gongxiong Yao3Hongchao Zhang4Chenghui Song5Xueren Ao6The Third Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaThe Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, ChinaPKMYT1 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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1605741/fullPKMYT1pancreatic cancervirtual screeningmolecular dynamicsexperimental validation |
| spellingShingle | Ting Wang Ting Wang Jingyu Wang Gongxiong Yao Hongchao Zhang Chenghui Song Xueren Ao Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer Frontiers in Pharmacology PKMYT1 pancreatic cancer virtual screening molecular dynamics experimental validation |
| title | Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer |
| title_full | Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer |
| title_fullStr | Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer |
| title_full_unstemmed | Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer |
| title_short | Structure-based discovery and experimental validation of HIT101481851 as a potential PKMYT1 inhibitor for pancreatic cancer |
| title_sort | structure based discovery and experimental validation of hit101481851 as a potential pkmyt1 inhibitor for pancreatic cancer |
| topic | PKMYT1 pancreatic cancer virtual screening molecular dynamics experimental validation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1605741/full |
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