De-Novo Designed Library of Benzoylureas as Inhibitors of BCL-XL: Synthesis, Structural and Biochemical Characterization
Details
Publication Year 2014-01-23, Volume 57, Issue #4, Page 1323-1343
Journal Title
Journal of medicinal chemistry
Publication Type
Journal Article
Abstract
The pro-survival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anti-cancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 muM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
Publisher
American Chemical Society
WEHI Research Division(s)
Structural Biology; Chemical Biology; Systems Biology And Personalised Medicine
Publisher's Version
https://doi.org/10.1021/jm401948b
NHMRC Grants
NHMRC/1025138
Rights Notice
Copyright © 2014 American Chemical Society


Creation Date: 2014-01-31 11:06:10
Last Modified: 2015-03-26 10:30:08
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