Advanced search×

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 E Sleebs, 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, and Jonathan B Baell

J Med Chem 54(6):1914-1926 (2011) PMID 21366295

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.

DOI: 10.1021/jm101596e
Version: za2963e q8zaa q8zba q8zc5 q8zd6 q8ze7 q8zf1 q8zg3
Buy PDF

Similar articles you may find interesting…

  1. ING4 regulates a secretory phenotype in primary fibroblasts with dual effects on cell proliferation and tumor growth.
    A Moreno, I Soleto, and I Palmero

    Oncogene (2013) PMID 23604125

    We have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize ch...
    Buy PDF
  2. Combined proteome and transcriptome analyses for the discovery of urinary biomarkers for urothelial carcinoma.
    N J Shimwell, R T Bryan, and D G Ward

    Br J Cancer (2013) PMID 23591195

    This 'dual-omic' strategy identified tumour secreted proteins whose urine concentrations are increased significantly by bladder cancer. Combined secretome-transcriptome analysis may be more useful than direct proteomic analysis of body fluids for biomarker discovery in both bladder cancer and other t...
    Buy PDF
  3. The dual role of fission yeast Tbc1/cofactor C orchestrates microtubule homeostasis in tubulin folding and as a GAP for GTPase Alp41/Arl2.
    Risa Mori and Takashi Toda

    Mol Biol Cell (2013) PMID 23576550

    We have identified the fission yeast cofactor - the ortholog of cofactor C, Tbc1. As well as its roles in tubulin folding, Tbc1 also has another role as a GAP in regulating Alp41/Arl2, a highly conserved small GTPase. Interestingly, the expression of either GDP- or GTP- bound Alp41 showed the identi...
    Buy PDF