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通过氨酸向和新化对突变选择性AKT抑制

Gregory B Craven¹, Hang Chu², Jessica D Sun²

¹Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.

|November 7, 2024

概括

研究人员开发了一种针对AKT1 (E17K) 突变的新型抑制剂,AKT1突变是许多癌症中常见的驱动因素. 这种突变选择性方法避免了其他AKT抑制剂所见的高血糖副作用,提供了一个有前途的新型癌症治疗方法.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

在各种固体瘤中,AKT1激酶的体质变异,特别是E17K突变,很普遍.
AKT1 E17K突变导致构成信号,驱动瘤发生.
现有的泛AKT抑制剂会导致剂量限制性高血糖症,需要开发突变选择性抑制剂.

研究的目的:

设计和开发针对AKT1 E17K突变的新型突变选择性抑制剂.
为了克服实现对野生类型AKT同类物具有选择性的挑战.
探索AKT1 (E17K) 驱动癌症的新疗法策略.

主要方法:

化物胺抑制剂的设计,化物胺抑制剂的设计,化物胺的化物胺的化物胺的化物胺的化物胺的化物胺的化物胺的化物.
抑制剂-酶复合物的结晶学分析.
在AKT1 (E17K) 异种移植模型中的体外和体内评估.
在细胞模型中评估Zn2+招募和抑制.

主要成果:

开发出具有AKT1 (E17K) 选择性的甲抑制剂.
通过抑制剂-激酶添加物发现了意想不到的Zn2+化,增强了持续的抑制.
在AKT1 (E17K) 瘤异位移植中已证明有效性,而不会诱导高血糖症.
通过向突变的氨酸和Zn2+化,实现了基于居住时间的精致选择性.

结论:

向AKT1 E17K突变 lysine 用甲抑制剂,加上 Zn2+ 化,提供了一个高度选择性的方法.
这一策略为治疗AKT1 (E17K) 驱动的癌症提供了潜在的治疗窗口,而无需剂量限制的高血糖症.
这些发现突出了实现突变特异性激酶抑制的新机制.

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