Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation
Simultaneous inhibition of two or more pathways is playing a crucial role in the treatment of hepatocellular carcinoma with complex and diverse pathogenesis. However, there have been no reports of dual-targeting inhibitors for protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) and hist...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1491497/full |
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| author | Yang Yang Yuting Wang Jing Chen Miao-Miao Niu Yongbin Wang Xing Jin |
| author_facet | Yang Yang Yuting Wang Jing Chen Miao-Miao Niu Yongbin Wang Xing Jin |
| author_sort | Yang Yang |
| collection | DOAJ |
| description | Simultaneous inhibition of two or more pathways is playing a crucial role in the treatment of hepatocellular carcinoma with complex and diverse pathogenesis. However, there have been no reports of dual-targeting inhibitors for protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) and histone deacetylase 2 (HDAC2), which are critical targets for hepatocellular carcinoma treatment. Here, an integrated strategy of virtual screening was utilized to identify dual-targeting inhibitors for PKMYT1 and HDAC2. Notably, PKHD-5 has been identified as a potent inhibitor that selectively targets both PKMYT1 and HDAC2 with nanomolar affinity. Molecular dynamics have confirmed the strong binding stability of PKHD-5 with PKMYT1 and HDAC2. Importantly, it displayed a notably lower IC50 against the HepG2/MDR cell line, underscoring its potential to surmount drug resistance, while exhibiting minimal toxicity towards the normal liver cell line L02. Additionally, PKHD-5 has demonstrated significant antitumor proliferation effects without significant toxicity. In summary, the results suggest that PKHD-5 is a promising candidate for further preclinical studies of hepatocellular carcinoma therapy. |
| format | Article |
| id | doaj-art-d02bc6eaeef64b15b41a08e6694482ae |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-d02bc6eaeef64b15b41a08e6694482ae2024-11-15T04:52:09ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-11-011510.3389/fphar.2024.14914971491497Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluationYang Yang0Yuting Wang1Jing Chen2Miao-Miao Niu3Yongbin Wang4Xing Jin5Department of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaDepartment of Laboratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, ChinaSimultaneous inhibition of two or more pathways is playing a crucial role in the treatment of hepatocellular carcinoma with complex and diverse pathogenesis. However, there have been no reports of dual-targeting inhibitors for protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) and histone deacetylase 2 (HDAC2), which are critical targets for hepatocellular carcinoma treatment. Here, an integrated strategy of virtual screening was utilized to identify dual-targeting inhibitors for PKMYT1 and HDAC2. Notably, PKHD-5 has been identified as a potent inhibitor that selectively targets both PKMYT1 and HDAC2 with nanomolar affinity. Molecular dynamics have confirmed the strong binding stability of PKHD-5 with PKMYT1 and HDAC2. Importantly, it displayed a notably lower IC50 against the HepG2/MDR cell line, underscoring its potential to surmount drug resistance, while exhibiting minimal toxicity towards the normal liver cell line L02. Additionally, PKHD-5 has demonstrated significant antitumor proliferation effects without significant toxicity. In summary, the results suggest that PKHD-5 is a promising candidate for further preclinical studies of hepatocellular carcinoma therapy.https://www.frontiersin.org/articles/10.3389/fphar.2024.1491497/fullhepatocellular carcinomaPKMYT1HDAC2dual-targeting inhibitorsvirtual screening |
| spellingShingle | Yang Yang Yuting Wang Jing Chen Miao-Miao Niu Yongbin Wang Xing Jin Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation Frontiers in Pharmacology hepatocellular carcinoma PKMYT1 HDAC2 dual-targeting inhibitors virtual screening |
| title | Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation |
| title_full | Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation |
| title_fullStr | Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation |
| title_full_unstemmed | Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation |
| title_short | Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation |
| title_sort | discovery of novel and highly potent dual targeting pkmyt1 hdac2 inhibitors for hepatocellular carcinoma through structure based virtual screening and biological evaluation |
| topic | hepatocellular carcinoma PKMYT1 HDAC2 dual-targeting inhibitors virtual screening |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1491497/full |
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