Quinazoline Sulfonamides as Dual Binders of the Proteins B-Cell Lymphoma 2 and B-Cell Lymphoma Extra Long with Potent Proapoptotic Cell-Based Activity
Details
Publication Year 2011-03-24, Volume 54, Issue #6, Page 1914-1926
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
Publication Type
Journal Article
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-xL 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.
Publisher
AMER CHEMICAL SOC
WEHI Research Division(s)
Chemical Biology; Structural Biology; Molecular Genetics Of Cancer
Publisher's Version
https://doi.org/10.1021/jm101596e
NHMRC Grants
NHMRC/461221 NHMRC/575561
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2011-03-24 12:00:00
Last Modified: 2015-03-24 10:01:03
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