Double-edged swords as cancer therapeutics: Novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway

Chunlin Zhuang, Zhenyuan Miao, Yuelin Wu, Zizhao Guo, Jin Li, Jianzhong Yao, Chengguo Xing, Chunquan Sheng, Wannian Zhang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)567-577
Number of pages11
JournalJournal of medicinal chemistry
Volume57
Issue number3
DOIs
StatePublished - Feb 13 2014

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