Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology

被引：12

作者：

Li, Kexue ^{[1
]}

机构：

[1] Amgen Inc, Dept Med Chem, Amgen Res, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 32卷

关键词：

Oncology; Protein-protein interactions; Pro-survival/anti-apoptotic; Anti-survival/pro-apoptotic; BCL-2; MCL-1; inhibitor; Structure-based drug design; Anticancer; ANTI-APOPTOTIC MCL-1; CHRONIC LYMPHOCYTIC-LEUKEMIA; FRAGMENT-BASED METHODS; BCL-2 FAMILY PROTEINS; HIGH-AFFINITY; IMMUNOHISTOCHEMICAL ANALYSIS; CANCER; DISCOVERY; POTENT; VENETOCLAX;

D O I：

10.1016/j.bmcl.2020.127717

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A hallmark of cancer is the evasion of apoptosis. Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates the mitochondrial apoptosis pathway. Over expression of MCL-1 contributes to oncogenesis and confers resistance to cancer treatments. Protein-protein interactions (PPI) are constitutive of the dynamic interplay between the proand anti-apoptotic proteins of the BCL-2 family, which is integral to controlling the apoptotic threshold of cells. Therapeutic intervention by small molecule BH3 mimetics to pharmacologically target the PPI and antagonize MCL-1 has made significant progress in recent years in oncology with multiple candidates entering clinical trials. This digest accounts the state-of-art MCL-1 inhibitors with emphasis on their discovery medicinal chemistry, highlighted in structure based drug design (SBDD) and biological evaluations.

引用

页数：13

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