Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway
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- 作者：Chunlin Zhuang ; Zhenyuan Miao ; Yuelin Wu ; Zizhao Guo ; Jin Li ; Jianzhong Yao ; Chengguo Xing ; Chunquan Sheng ; Wannian Zhang
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：February 13, 2014
- 年：2014
- 卷：57
- 期：3
- 页码：567-577
- 全文大小：467K
- ISSN：1520-4804
文摘
Simultaneous inactivation of p53 and hyperactivation of nuclear factor-魏B (NF-魏B) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-魏B. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53鈥揗DM2 interaction and NF-魏B pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53鈥揗DM2 interaction and NF-魏B pathway. Most of the compounds were identified to possess nanomolar p53鈥揗DM2 inhibitory activity. Compounds 5q and 5s suppressed NF-魏B activation through inhibition of I魏B伪 phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKK伪/尾. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-魏B pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).