双酸盐生成的ATP类型抑制细胞信号通路
Satish R Malwal1, Bing O'Dowd1, Xinxin Feng1
1Department of Chemistry , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
Journal of the American Chemical Society
|May 23, 2018
概括
用于骨质疏松症和癌症的双酸盐通过形成ATP类似物来抑制激酶. 新的双酸盐前期药物产生强大的激酶抑制剂,促进治疗骨疾病和癌症的药物开发.
科学领域:
- 生物化学
- 药理学
- 医学化学
背景情况:
- 双酸盐是骨质疏松症,帕杰特病和癌症的关键疗法.
- 建议的作用机制包括抑制蛋白质前化,EGFR或腺核酸转位酶.
- 腺核酸转位酶抑制涉及细胞形成的ATP类似物,如ApppI和AppCCl2p.
研究的目的:
- 研究二酸衍生ATP类型的激酶抑制特征.
- 探索双酸盐前药物作为新激酶抑制剂的潜力.
- 阐明双酸介导激酶抑制的分子相互作用.
主要方法:
- 对ApppI和AMP-clodronate (AppCCl2p) 的选与369个激酶组进行了对比.
- 双酸盐前药物的合成和细胞评估.
- 对激酶抑制和细胞信号通路调节的分析.
主要成果:
- 显示AppCCl2p对某些类铁酶有强烈的抑制作用,这种抑制作用归因于与铁残留物的结合.
- 合成的双酸盐前药物被细胞内转化为ATP类似物.
- 这些新型类似物作为低纳米激酶抑制剂,有效抑制细胞信号通路.
结论:
- 这些发现澄清了双酸盐作为激酶抑制剂的作用机制.
- 双酸盐前期药物是开发新疗法的一种有希望的策略.
- 这项研究为针对骨吸收,癌症和炎症的新药开辟了道路.
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