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

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

  • J Med Chem. 2011 Mar 24;54(6):1914-26. doi: 10.1021/jm101596e.
Brad E Sleebs 1,  Peter E Czabotar,  Wayne J Fairbrother,  W Douglas Fairlie,  John A Flygare,  David C S Huang,  Wilhelmus J A Kersten,  Michael F T Koehler,  Guillaume Lessene,  Kym Lowes,  John P Parisot,  Brian J Smith,  Morey L Smith,  Andrew J Souers,  Ian P Street,  Hong Yang,  Jonathan B Baell
Affiliations

Affiliation

  • 1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
PMID: 21366295 DOI: 10.1021/jm101596e
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.

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