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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1467028
This article is part of the Research Topic New Insights Into Post-translational Modification of Proteins & Immune Regulation in Carcinogenesis, Heart Disease, Neurodegenerative Disorders, and Allergic Diseases-Volume II View all 3 articles

Design, Synthesis, and Biological Evaluation of 2,4dimorpholinopyrimidine-5-carbonitrile derivatives as Orally Bioavailable PI3K inhibitors

Provisionally accepted
Huang Daowei Huang Daowei 1*Yang Jixia Yang Jixia 2Zhang Qingwei Zhang Qingwei 3Zhou Xiaolei Zhou Xiaolei 1Shang Zhenhua Shang Zhenhua 1Li Jianqi Li Jianqi 3Zhang Baoyin Zhang Baoyin 4
  • 1 Hebei University of Science and Technology, Shijiazhuang, China
  • 2 Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
  • 3 China State Institute of Pharmaceutical Industry, Shanghai, Shanghai Municipality, China
  • 4 Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China

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

    Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity. In this study, we designed and synthesized a series of 2,4dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency. Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC50: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC50: 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC50: 15.4 ± 1.9 nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests, while having outstanding liver microsomal stability in vitro, with half-lives of 38.5 min in rats and 127.9 min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780.In a pharmacokinetic study, 17p was stable (T½: 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment.

    Keywords: PI3Ks, 2, 4-dimorpholinopyrimidine-5-carbonitrile, Synthesis, anti-cancer, bioavailability

    Received: 19 Jul 2024; Accepted: 19 Sep 2024.

    Copyright: © 2024 Daowei, Jixia, Qingwei, Xiaolei, Zhenhua, Jianqi and Baoyin. 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: Huang Daowei, Hebei University of Science and Technology, Shijiazhuang, 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.