Discovery of Potent and Selective Benzothiazole Hydrazone Inhibitors of Bcl-XL
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- 作者：Brad E. Sleebs ; Wilhemus J. A. Kersten ; Sanji Kulasegaram ; George Nikolakopoulos ; Effie Hatzis ; Rebecca M. Moss ; John P. Parisot ; Hong Yang ; Peter E. Czabotar ; W. Douglas Fairlie ; Erinna F. Lee ; Jerry M. Adams ; Lin Chen ; Mark F. van Delft ; Kym N. Lowes ; Andrew Wei ; David C.S. Huang ; Peter M. Colman ; Ian P. Street ; Jonathan B. Baell ; Keith Watson ; Guillaume Lessene
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：July 11, 2013
- 年：2013
- 卷：56
- 期：13
- 页码：5514-5540
- 全文大小：1055K
- 年卷期：v.56,no.13(July 11, 2013)
- ISSN：1520-4804
文摘
Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-XL and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.