Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1491497

Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation

Provisionally accepted
Yang Yang Yang Yang 1Yuting Wang Yuting Wang 2Jing Chen Jing Chen 1Miao-Miao Niu Miao-Miao Niu 2Yongbin Wang Yongbin Wang 1Xing Jin Xing Jin 1*
  • 1 The Affiliated Hospital of Yangzhou University, Yangzhou, China
  • 2 China Pharmaceutical University, Nanjing, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    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.

    Keywords: Hepatocellular Carcinoma, PKMYT1, HDAC2, dual-targeting inhibitors, Virtual Screening

    Received: 05 Sep 2024; Accepted: 05 Nov 2024.

    Copyright: © 2024 Yang, Wang, Chen, Niu, Wang and Jin. 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: Xing Jin, The Affiliated Hospital of Yangzhou University, Yangzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.