title: A novel drug discovery strategy: mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-κB pathways.
abstract: The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. In this study, we report an antitumor molecule that bears a pyrrolo[3,4-c]pyrazole scaffold and functions as an enantiomeric inhibitor against both the p53-MDM2 interaction and the NF-κB activation. It is a first-in-class enantiomeric inhibitor with dual efficacy for cancer therapy. Synergistic effect was observed in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China. Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, 55455, Minnesota.
authors.forename: Woo Shik
authors.initials: WS
authors.lastname: Shin
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.affiliation: Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, 55455, Minnesota.
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Sham
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000600792:5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-1-(4-fluorobenzyl)-3-phenyl-4,5-dihydropyrrolo(3,4-c)pyrazol-6(1H)-one; D000970:Antineoplastic Agents; D016328:NF-kappa B; D011720:Pyrazoles; D011760:Pyrrolidinones; D016159:Tumor Suppressor Protein p53; C031280:pyrazole; D051736:Proto-Oncogene Proteins c-mdm2