期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 35, 页码 10446-10450出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201705008
关键词
apoptosis; drug discovery; medicinal chemistry; protein-protein interactions; solid-phase synthesis
资金
- EPSRC [EP/M006379/1]
- Engineering and Physical Sciences Research Council [EP/M006379/1] Funding Source: researchfish
- EPSRC [EP/M006379/1] Funding Source: UKRI
Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective alpha-helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl-1, commonly exploited by cancers to avoid cell death. Peptide-directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC50 value of less than 100 mu m, and approximately 25 % had IC50 values below 1 mu m to Mcl-1. Compounds show selectivity for Mcl-1 over other anti-apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new alpha-helical PPI modulators.
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