Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain
Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain
复制标题
DOI：
10.1038/nchembio.2174
复制
发表时间：
2016-11-01
影响因子：
14.8
通讯作者：
Su, Qibin
中科院分区：
文献类型：
--
作者：
Akcay, Gizem;Belmonte, Matthew A.;Su, Qibin
靶向共价抑制疾病相关蛋白已成为药物发现领域的一种强有力的方法，导致新疗法的批准。然而，目前的方法往往是有限的，因为它们依赖于半胱氨酸残基来产生共价键。在这里，我们使用芳基硼酸羰基弹头共价靶向非催化性赖氨酸侧链，并产生了我们所知的第一个可逆的Mcl-1共价抑制剂，Mcl-1是一种蛋白质-蛋白质相互作用（PPI）靶点，已被证明难以通过传统的药物化学策略抑制。与非共价同源物相比，这些共价结合剂表现出改善的效力，如在生物化学和基于细胞的测定中所证明的。我们确定Lys234作为参与共价修饰的残基，通过点突变。本研究中发现的共价结合剂将作为开发Mcl-1治疗剂和探针以询问Mcl-1依赖性生物现象的有用起点。
Targeted covalent inhibition of disease-associated proteins has become a powerful methodology in the field of drug discovery, leading to the approval of new therapeutics. Nevertheless, current approaches are often limited owing to their reliance on a cysteine residue to generate the covalent linkage. Here we used aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain, and generated to our knowledge the first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies. These covalent binders exhibited improved potency in comparison to noncovalent congeners, as demonstrated in biochemical and cell-based assays. We identified Lys234 as the residue involved in covalent modification, via point mutation. The covalent binders discovered in this study will serve as useful starting points for the development of Mcl-1 therapeutics and probes to interrogate Mcl-1-dependent biological phenomena.