Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53-MDM2 Interaction and the NF-kappa B Pathway

作者：Zhuang Chunlin; Miao Zhenyuan^*; Wu Yuelin; Guo Zizhao; Li Jin; Yao Jianzhong; Xing Chengguo; Sheng Chunquan; Zhang Wannian

来源：Journal of Medicinal Chemistry, 2014, 57(3): 567-577.

DOI：10.1021/jm401800k

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-kappa B (NF-kappa B) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-kappa 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-MDM2 interaction and NF-kappa 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-MDM2 interaction and NF-kappa B pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-kappa B activation through inhibition of I kappa B alpha phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKK alpha/beta. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-kappa 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%).

• 出版日期2014-2-13
• 单位中国人民解放军第二军医大学