Journal article

Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X-L and BCL-2

Michael J Roy, Amelia Vom, Toru Okamoto, Brian J Smith, Richard W Birkinshaw, Hong Yang, Houda Abdo, Christine A White, David Segal, David CS Huang, Jonathan B Baell, Peter M Colman, Peter E Czabotar, Guillaume Lessene



The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exp..

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Awarded by National Health and Medical Research Council (NHMRC)

Awarded by Leukemia and Lymphoma Society (Specialized Center of Research Grants)

Awarded by Cancer Council of Victoria

Awarded by NHMRC

Funding Acknowledgements

This work was supported by fellowships and grants from the Australian Government (Australian Postgraduate Award to M.J.R.), the Australian Research Council (fellowship to P.E.C.), the National Health and Medical Research Council (NHMRC, fellowships to P.E.C., G.L., D.C.S.H., B.J.S., J.B.B., 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 is gratefully acknowledged.