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J Med Chem. 2011 Mar 24;54(6):1914-26. doi: 10.1021/jm101596e. Epub 2011 Mar 2.

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

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The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.


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-x(L) 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.

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