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
  • 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.