Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

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• 作者：Milan Bruncko ; Thorsten K. Oost ; Barbara A. Belli ; Hong Ding ; Mary K. Joseph ; Aaron Kunzer ; Darlene Martineau ; William J. McClellan ; Michael Mitten ; Shi-Chung Ng ; Paul M. Nimmer ; Tilman Oltersdorf ; Ch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 22, 2007
• 年：2007
• 卷：50
• 期：4
• 页码：641 - 662
• 全文大小：755K
• 年卷期：v.50,no.4(February 22, 2007)
• ISSN：1520-4804

文摘

Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through whichcancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition ofthese prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discoveryof a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Herewe describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surfaceof these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminatedin the identification of 2, which exhibited EC₅₀ values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependentcells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphomacell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given bothas a single agent and in combination with etoposide.