Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA.
School of Chemistry, Cardiff University, Cardiff, CF10 3AT, UK.
ChemMedChem. 2020 Sep 16;15(18):1691-1698. doi: 10.1002/cmdc.202000278. Epub 2020 Jun 25.
Protein-protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.
蛋白质-蛋白质相互作用（PPIs），其中许多受 α-螺旋识别结构域主导，在许多重要的细胞过程中发挥关键作用，这些相互作用的失调会产生有害影响。例如，涉及 Bcl-2 蛋白家族的异常 PPI 可导致多种疾病，包括癌症、神经退行性疾病和糖尿病。Bcl-2 生存蛋白（如 Mcl-1）和死亡促进蛋白（如 Bim）之间的相互作用调节细胞凋亡的内在途径。肿瘤抑制蛋白 p53 在细胞凋亡中也具有关键作用，其受其 E3 泛素连接酶 HDM2 的负调控。Mcl-1 和 HDM2 在许多癌症中均上调，有趣的是，这两种蛋白途径之间存在串扰。最近，已经观察到 Mcl-1 和 HDM2 抑制剂之间的协同作用。为了开发新的抗癌药物，我们在此描述了一种多药理学方法，通过使用三个密集功能化的异噁唑、吡唑和噻唑作为其伴侣蛋白关键 α-螺旋结构域的模拟物，对 Mcl-1 和 HDM2 进行双重抑制。
