Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity

BE Sleebs; PE Czabotar; WJ Fairbrother; WD Fairlie; JA Flygare; DCS Huang; WJA Kersten; MFT Koehler; G Lessene; K Lowes; JP Parisot; BJ Smith; ML Smith; AJ Souers; IP Street; H Yang; JB Baell

Journal article

Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity

BE Sleebs, PE Czabotar, WJ Fairbrother, WD Fairlie, JA Flygare, DCS Huang, WJA Kersten, MFT Koehler, G Lessene, K Lowes, JP Parisot, BJ Smith, ML Smith, AJ Souers, IP Street, H Yang, JB Baell

Journal of Medicinal Chemistry | Published : 2011

DOI: 10.1021/jm101596e

Abstract

ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-xL and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-xL that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second know..

View full abstract

University of Melbourne Researchers

Brad Sleebs Author

Peter Czabotar Author

David Huang Author

Guillaume Lessene Author

Grants

Awarded by Leukemia and Lymphoma Society

Awarded by NHMRC

Awarded by NHMRC IRIISS

Funding Acknowledgements

This work was supported by Fellowships and Grants from the Leukemia and Lymphoma Society (SCOR 7015-02). Crystallization trials were performed at the Bio21 Collaborative Crystallisation Centre, Victoria, Australia. We thank Peter Colman for useful discussions and also the NHMRC, the Victorian State Government, the Cancer Council of Victoria, the Australian Cancer Research Foundation, and the Australian Research Council for the following support: NHMRC Program Grant 461221; NHMRC IRIISS Grant #361646; Victorian State Government OIS grant; Cancer Council of Victoria, Fraser Fellowship to P. M. Colman (2002-2006); ACRE Equipment Grant (2002); ARC Future Fellowship; and NHMRC Project Grant 575561 to P.E.C.