抑制MTH1通过阻止dNTP池的卫生,消除了癌症
Helge Gad1, Tobias Koolmeister1, Ann-Sofie Jemth1
11] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2].
癌细胞依赖MTH1蛋白来防止DNA受氧化核酸损伤. 用新型化合物TH287和TH588抑制MTH1导致癌细胞死亡,验证了MTH1作为有前途的抗癌标.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 生物化学 生物化学
背景情况:
- 癌细胞表现出氧化还原失调,产生破坏DNA和脱氧核酸三酸盐 (dNTP) 的反应性氧物种.
- MTH1蛋白在消毒氧化dNTP池中起着至关重要的作用,防止DNA复制过程中损坏的基质被纳入.
研究的目的:
- 研究MTH1在癌细胞中的关键性及其作为抗癌治疗点的潜力.
- 确定和描述MTH1.1的新型小分子抑制剂.
主要方法:
- 利用基于细胞的测试来评估癌细胞中MTH1的依赖性.
- 开发并描述了小分子TH287和TH588作为MTH1抑制剂.
- 确定MTH1与抑制剂的共同晶体结构.
- 在患者衍生的老鼠异种移植中评估了体内疗效.
主要成果:
- 与正常细胞不同,癌细胞非常依赖MTH1活动来防止DNA损伤和细胞死亡.
- 小分子TH287和TH588在细胞中强烈而有选择地抑制MTH1.
- 抑制剂结合结构在MTH1活性部位内确认结合.
- 用TH287/TH588治疗导致氧化dNTP的结合,DNA损伤,细胞毒性和体内治疗反应.
结论:
- MTH1是一种特定于癌症的脆弱性,对癌细胞存活至关重要.
- MTH1 抑制剂 TH287 和 TH588 代表了一种新型的抗癌药物.
- 这项研究验证了非基因成概念和MTH1作为癌症表型致命目标.
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