Huang Daowei, Yang Jixia, Zhang Qingwei, Zhou Xiaolei, Wang Yanbo, Shang Zhenhua, Li Jianqi, Zhang Baoyin
School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, China.
Hebei Research Center of Pharmaceutical and Chemical Engineering, Shijiazhuang, China.
Front Pharmacol. 2024 Oct 21;15:1467028. doi: 10.3389/fphar.2024.1467028. eCollection 2024.
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 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency.
Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC: 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC: 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 , 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 ( : 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment.
磷酸肌醇-3-激酶（PI3K）在许多肿瘤中过表达，因此是癌症治疗的理想靶点。因此，迫切需要开发高效低毒的PI3K抑制剂。
在本研究中，我们设计并合成了一系列2,4-二吗啉基嘧啶-5-腈衍生物，并对其PI3K抑制活性进行了评估。
化合物17p表现出与阳性对照BKM-120相当的PI3Kα抑制活性（IC：31.8±4.1 nM）（IC：44.6±3.6 nM）。此外，17p对PI3Kδ表现出显著的抑制活性（IC：15.4±1.9 nM），对PI3Kβ、PI3Kγ和mTOR具有显著的亚型选择性。此外，17p在Ames试验和hERG试验中对癌细胞活性表现出良好的抗增殖活性和良好的安全性，同时具有出色的肝微粒体稳定性，在大鼠中的半衰期为3... 展开
