Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors

被引：16

作者：

Luan, Shenglin ^{[1
]}

Ge, Qj ^{[1
]}

Chen, Yedong ^{[1
]}

Dai, Mingyang ^{[1
]}

Yang, Jinyu ^{[1
]}

Li, Kun ^{[1
]}

Liu, Dan ^{[1
]}

Zhao, Linxiang ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drugs Design & Discovery, Shenyang 110016, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 09期

基金：

中国国家自然科学基金;

关键词：

Apoptosis; Bcl-2; Mcl-1; Structure-based design; STRUCTURE-BASED DESIGN; CANCER; POTENT; RESISTANCE; APOPTOSIS; LEUKEMIA; ABT-199; ABT-263; COMBINATION; VENETOCLAX;

D O I：

10.1016/j.bmcl.2017.03.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (24((2-carbamoyl-1-(3-(4-methoxyphenoxy)propy1)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited K-j value of 110 nM for interfering Mcl-1 binding was obtained after hit-to-lead modification. (C) 2017 Published by Elsevier Ltd.

引用

页码：1943 / 1948

页数：6

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