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Quinazoline Sulfonamides as Dual Binders of the Proteins B-Cell Lymphoma 2 and B-Cell Lymphoma Extra Long with Potent Proapoptotic Cell-Based Activity


Sleebs, BE; Czabotar, PE; Fairbrother, WJ; Fairlie, WD; Flygare, JA; Huang, DCS; Kersten, WJA; Koehler, MFT; Lessene, G; Lowes, K; Parisot, JP; Smith, BJ; Smith, ML; Souers, AJ; Street, IP; Yang, H; Baell, JB
2011-03-24
JOURNAL OF MEDICINAL CHEMISTRY
Journal Article
54
6
1914-1926
ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) 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 known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
AMER CHEMICAL SOC
Chemical Biology ; Structural Biology ; Molecular Genetics of Cancer
10.1021/jm101596e
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Creation Date 2011-03-24 12:00:00 Last Modified 2015-03-24 10:01:03