美国加州大学旧金山分校Jack Taunton课题组，通过靶向赖氨酸和新型锌螯合实现突变选择性AKT抑制。2024年11月6日，《自然》杂志在线发表了这项成果。

研究人员表示，在多种实体肿瘤中已发现致癌激酶AKT1的体细胞变异。最常见的AKT1变异是将调节性pleckstrin同源域中的谷氨酸17（Glu17）替换为赖氨酸（Lys）（E17K），导致其恒定的膜定位和致癌信号的激活。在临床研究中，广谱AKT抑制剂被发现会导致剂量限制性的高血糖症，这促使了选择性突变抑制剂的研究。

研究人员利用E17K突变设计了靶向赖氨酸的异构调控型水杨醛抑制剂，对AKT1（E17K）具有选择性，而不作用于野生型AKT同源物。鉴于在变构位点附近存在三个保守的赖氨酸，这一目标具有重大挑战。

晶体学分析表明，抑制剂复合物中意外地发现了一个四面体锌离子，它协调了激酶激活环中的两个邻近半胱氨酸，同时与E17K–亚胺复合物结合。水杨醛亚胺复合物与AKT1（E17K）结合时，但不是与野生型AKT1结合时，能在细胞中招募内源性Zn²⁺，从而实现持续的抑制作用。

在AKT1（E17K）肿瘤异种移植模型中，这种水杨醛类抑制剂在不引起高血糖症的剂量下具有疗效。该研究表明，通过靶向突变的赖氨酸并结合Zn²⁺螯合，所生成的水杨醛亚胺加合物可以实现对AKT1（E17K）极为精确的停留时间选择性。

附：英文原文

Title: Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

Author: Craven, Gregory B., Chu, Hang, Sun, Jessica D., Carelli, Jordan D., Coyne, Brittany, Chen, Hao, Chen, Ying, Ma, Xiaolei, Das, Subhamoy, Kong, Wayne, Zajdlik, Adam D., Yang, Kin S., Reisberg, Solomon H., Thompson, Peter A., Lipford, J. Russell, Taunton, Jack

Issue&Volume: 2024-11-06

Abstract: Somatic alterations in the oncogenic kinase AKT1 have been identified in a broad spectrum of solid tumours. The most common AKT1 alteration replaces Glu17 with Lys (E17K) in the regulatory pleckstrin homology domain1, resulting in constitutive membrane localization and activation of oncogenic signalling. In clinical studies, pan-AKT inhibitors have been found to cause dose-limiting hyperglycaemia2,3,4,5,6, which has motivated the search for mutant-selective inhibitors. We exploited the E17K mutation to design allosteric, lysine-targeted salicylaldehyde inhibitors with selectivity for AKT1 (E17K) over wild-type AKT paralogues, a major challenge given the presence of three conserved lysines near the allosteric site. Crystallographic analysis of the covalent inhibitor complex unexpectedly revealed an adventitious tetrahedral zinc ion that coordinates two proximal cysteines in the kinase activation loop while simultaneously engaging the E17K–imine conjugate. The salicylaldimine complex with AKT1 (E17K), but not that with wild-type AKT1, recruits endogenous Zn2+ in cells, resulting in sustained inhibition. A salicylaldehyde-based inhibitor was efficacious in AKT1 (E17K) tumour xenograft models at doses that did not induce hyperglycaemia. Our study demonstrates the potential to achieve exquisite residence-time-based selectivity for AKT1 (E17K) by targeting the mutant lysine together with Zn2+ chelation by the resulting salicylaldimine adduct.

DOI: 10.1038/s41586-024-08176-4

Source: https://www.nature.com/articles/s41586-024-08176-4