A Potent Bivalent Smac Mimetic (SM-1200) Achieving Rapid, Complete, and Durable Tumor Regression in Mice

详细信息    查看全文

• 作者：Rong Sheng ; Haiying Sun ; Liu Liu ; Jianfeng Lu ; Donna McEachern ; Guanfeng Wang ; Jianfeng Wen ; Ping Min ; Zhenyun Du ; Huirong Lu ; Sanmao Kang ; Ming Guo ; Dajun Yang ; Shaomeng Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3969-3979
• 全文大小：581K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

We have designed, synthesized, and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1, and cIAP2 with K_i values of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC₅₀ values of 11.0 and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.