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

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.

authors

  • Sleebs, Brad E
  • Czabotar, Peter E
  • Fairbrother, Wayne J
  • Fairlie, W Douglas
  • Flygare, John A
  • Huang, David CS
  • Kersten, Wilhelmus JA
  • Koehler, Michael FT
  • Lessene, Guillaume
  • Lowes, Kym
  • Parisot, John P
  • Smith, Brian J
  • Smith, Morey L
  • Souers, Andrew J
  • Street, Ian P
  • Yang, Hong
  • Baell, Jonathan B

publication date

  • March 24, 2011

has subject area