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

[Display omitted] Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-05, Vol.27 (9), p.1943-1948
Main Authors: Luan, Shenglin, Ge, Qi, Chen, Yedong, Dai, Mingyang, Yang, Jinyu, Li, Kun, Liu, Dan, Zhao, Linxiang
Format: Article
Language:English
Subjects:
Apoptosis
Bcl-2
Cell Line, Tumor
Drug Design
Humans
Indoles - chemistry
Indoles - pharmacology
Mcl-1
Molecular Docking Simulation
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Protein Binding - drug effects
Structure-Activity Relationship
Structure-based design
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Summary:[Display omitted] Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-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 Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.03.028