title: Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway.
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%).
authors.affiliation: School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Wu
authors.forename: Zizhao
authors.initials: Z
authors.lastname: Guo
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011720:Pyrazoles; D011758:Pyrroles; D011760:Pyrrolidinones; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2