Discovery of pyrimidine-2,4-diamine analogues as efficiency anticancer drug by targeting GTSE1

• Published in: Bioorganic chemistry 2024-10, Vol.151, p.107700, Article 107700
• Main Authors: Xing, Sunhui, Yang, Huamao, Chen, Xiaojian, Wang, Yan, Zhang, Shuyuan, Wang, Peipei, Chen, Chaoyue, Wang, Kun, Liu, Zhiguo, Zheng, Xiaohui
• Format: Article
• Language: English
• Subjects: Animals; Anticancer efficacy; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Diamines - chemical synthesis; Diamines - chemistry; Diamines - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; GTSE1; Humans; Mice; Mice, Nude; Molecular Structure; Pyrimidine-2,4-diamine derivatives; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107700

Y18 demonstrated potent inhibitory effects on cancer cell proliferation and migration by selectively suppressing GTSE1 expression. [Display omitted] •GTSE1 was confirmed as a potent anticancer target in CRC and NSCLC.•A series of pyrimidine-2,4-diamine derivatives were synthesized.•Y18 exhibited anticancer efficacy by inhibiting transcription and expression of GTSE1.•Y18 exhibited significantly anticancer efficacy both in vitro and in vivo.•Y18 has high biosafety for organs and suitable oral bioavailability (16.27%). A series of pyrimidine-2,4-diamine analogues were designed and synthesized. Their anticancer activity and the underlying mechanism against colorectal cancer (CRC) HCT116 cells and non-small cell lung cancer (NSCLC) A549 cells were investigated. The results demonstrated that the active compound Y18 significantly inhibited cancer cell proliferation by inducing robust cell cycle arrest and cell senescence through the persistence of DNA damage. Additionally, Y18 exhibited significant inhibitory effects on the adhesion, migration and invasion of cancer cells in vitro. Mechanistically, Y18 achieved these anticancer activities by suppressing GTSE1 transcription and expression. Y18 also effectively inhibited tumor growth in vivo with minimal side effects. Furthermore, Y18 exhibited a suitable half-life and oral bioavailability (16.27%), with limited inhibitory activity on CYP isoforms. Taken together, these results suggested that Y18 could be a potential chemotherapeutic drug for cancer treatment, particularly in cases of GTSE1 overexpressed cancers.