De-Novo Designed Library of Benzoylureas as Inhibitors of BCL-XL: Synthesis, Structural and Biochemical Characterization
- Author(s)
- Brady, RM; Vom, A; Roy, MJ; Toovey, N; Smith, BJ; Moss, RM; Hatzis, E; Huang, DCS; Parisot, JP; Yang, H; Street, IP; Colman, PM; Czabotar, PE; Baell, JB; Lessene, G;
- 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
- 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,
- Terms of Use/Rights Notice
- Copyright © 2014 American Chemical Society
Creation Date: 2014-01-31 11:06:10
Last Modified: 2015-03-26 10:30:08