De-novo designed library of benzoylureas as inhibitors of BCL-X L: Synthesis, structural and biochemical characterization

RM Brady; A Vom; MJ Roy; N Toovey; BJ Smith; RM Moss; E Hatzis; DCS Huang; JP Parisot; H Yang; IP Street; PM Colman; PE Czabotar; JB Baell; G Lessene

Journal article

De-novo designed library of benzoylureas as inhibitors of BCL-X L: Synthesis, structural and biochemical characterization

RM Brady, A Vom, MJ Roy, N Toovey, BJ Smith, RM Moss, E Hatzis, DCS Huang, JP Parisot, H Yang, IP Street, PM Colman, PE Czabotar, JB Baell, G Lessene

Journal of Medicinal Chemistry | Published : 2014

DOI: 10.1021/jm401948b

Abstract

The prosurvival 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 anticancer 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 μM) and selectivity for BCL-XL...

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University of Melbourne Researchers

David Huang Author

Peter Colman Author

Peter Czabotar Author

Guillaume Lessene Author

Grants

Awarded by Australian Cancer Research Foundation

Funding Acknowledgements

We thank our colleagues at WEHI for their work on the BCL-2 family of proteins that has led to this contribution and for discussions during this work, in particular, Andreas Strasser and Suzanne Cory. This work was supported by fellowships and grants from the Australian Research Council (fellowship to P.E.C.), the National Health and Medical Research Council (NHMRC, fellowships to J.B.B. and P.M.C.; Project Grant GNT1025138; Development Grant 305536; and Program Grants 257502, 461221, and 1016701), the Leukemia and Lymphoma Society (Specialized Center of Research Grants 7015 and 7413), the Cancer Council of Victoria (fellowship to P.M.C., Grant-in-Aid 461239), and the Australian Cancer Research Foundation. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme Grant 361646 and a Victorian State Government OIS grant are gratefully acknowledged.