通过靶向 GTSE1 发现嘧啶-2,4-二胺类似物作为高效抗癌药物。
Discovery of pyrimidine-2,4-diamine analogues as efficiency anticancer drug by targeting GTSE1.
发表日期：2024 Aug 08
作者：
Sunhui Xing, Huamao Yang, Xiaojian Chen, Yan Wang, Shuyuan Zhang, Peipei Wang, Chaoyue Chen, Kun Wang, Zhiguo Liu, Xiaohui Zheng
来源：
BIOORGANIC CHEMISTRY
摘要：
设计并合成了一系列嘧啶-2,4-二胺类似物。研究了它们的抗癌活性以及针对结直肠癌 (CRC) HCT116 细胞和非小细胞肺癌 (NSCLC) A549 细胞的潜在机制。结果表明，活性化合物 Y18 通过持续 DNA 损伤诱导细胞周期停滞和细胞衰老，从而显着抑制癌细胞增殖。此外，Y18在体外对癌细胞的粘附、迁移和侵袭表现出显着的抑制作用。从机制上讲，Y18 通过抑制 GTSE1 转录和表达来实现这些抗癌活性。 Y18 还可以有效抑制体内肿瘤生长，且副作用极小。此外，Y18 表现出合适的半衰期和口服生物利用度（16.27%），对 CYP 亚型的抑制活性有限。总而言之，这些结果表明 Y18 可能是一种潜在的癌症化疗药物，特别是在 GTSE1 过度表达的癌症中。版权所有 © 2024 Elsevier Inc. 保留所有权利。
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.Copyright © 2024 Elsevier Inc. All rights reserved.