title: Distinct novel quinazolinone exhibits selective inhibition in MGC-803 cancer cells by dictating mutant p53 function.
abstract: The mutant p53 proteins and their corresponding cellular response can be manipulated by novel quinazolinone derivatives 4-8 (a-i) in p53 mutant cancer cells. Of the two most potent compounds, 4a exhibited promising broad-spectrum anti-cancer effects, whereas 6c showed selective and exclusive inhibition activity in p53 mutant cancer cell lines but low toxicity to wild-type p53 cancer cell A375 and normal lung fibroblast WI-38 cells. Furthermore, 6c exhibited a more sophisticated mechanism for cell-destructive response by causing S/G2 phase arrest effect and cell size reduction. Compared with the cellular response of 6b and genetic background of cell lines studied, p53 mutation was found to be the key factor and main target for 6c evoked cell-destructive response. Molecular mechanism studies indicated that p53 phosphorylation and acetylation dual-targeting inhibitor 6c exerted anti-cancer activities with a special mechanism in evoking cell apoptosis by arresting mutant p53 function to trigger the deregulation of Cdk2 caused Bim-mediated apoptosis. To the best of our knowledge, 6c is the first quinazolinone derivative to dictate mutant p53 function for apoptotic cell death.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Guo-Hai
authors.initials: GH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Xue
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: An
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Jing-Mei
authors.initials: JM
authors.lastname: Yuan
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China.
authors.forename: Jiang-Ke
authors.initials: JK
authors.lastname: Qin
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China. Electronic address: chengxuepan@163.com.
authors.forename: Cheng-Xue
authors.initials: CX
authors.lastname: Pan
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Science and Technology of China), School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, PR China. Electronic address: gfysglgx@163.com.
authors.forename: Gui-Fa
authors.initials: GF
authors.lastname: Su
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones; D016159:Tumor Suppressor Protein p53; D051357:Cyclin-Dependent Kinase 2
keywords: Apoptosis; Mutant p53; Quinazolinone; Selective inhibition