Quinazoline Sulfonamides as Dual Binders of the Proteins B-Cell Lymphoma 2 and B-Cell Lymphoma Extra Long with Potent Proapoptotic Cell-Based Activity
详细信息 查看全文
- 作者：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 ; Jonathan B. Baell
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：March 24, 2011
- 年：2011
- 卷：54
- 期：6
- 页码：1914-1926
- 全文大小：1082K
- 年卷期：v.54,no.6(March 24, 2011)
- ISSN：1520-4804
文摘
ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-xL 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.