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

Brad Sleebs, Peter Edward Czabotar, Wayne J Fairbrother, W Douglas Fairlie, John A Flygare, David CS Huang, Wilhelmus J A Kersten, Michael F T Koehler, Guillaume Lessene, Kym N Lowes, John P Parisot, Brian J Smith, Morey L Smith, Andrew J Souers, Ian Philip Street, Hong Yang, Jonathan Bayldon Baell

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55 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1914 - 1926
Number of pages13
JournalJournal of Medicinal Chemistry
Volume54
Issue number6
DOIs
Publication statusPublished - 2011
Externally publishedYes

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