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

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

  • Bioorg Chem. 2024 Oct:151:107700. doi: 10.1016/j.bioorg.2024.107700.
Sunhui Xing 1,  Huamao Yang 1,  Xiaojian Chen 1,  Yan Wang 1,  Shuyuan Zhang 1,  Peipei Wang 1,  Chaoyue Chen 1,  Kun Wang 2,  Zhiguo Liu 3,  Xiaohui Zheng 4
Affiliations

Affiliations

  • 1 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
  • 2 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: kunwang224@163.com.
  • 3 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: lzgcnu@163.com.
  • 4 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; The Key Laboratory of Pediatric Hematology and oncology Diseases of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: zhengxh@wmu.edu.cn.
PMID: 39128245 DOI: 10.1016/j.bioorg.2024.107700
Abstract

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.

Keywords

Anticancer efficacy; Cell migration; Cell proliferation; GTSE1; Pyrimidine-2,4-diamine derivatives.

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