title: Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer.
abstract: Mouse double minute 2 (MDM2) protein functionally inactivates the tumor suppressor p53 in human cancer. Conventional MDM2 inhibitors provide limited clinical application as they interfere only with the MDM2-p53 interaction to release p53 from MDM2 sequestration but do not prevent activated p53 from transcriptionally inducing MDM2 expression. Here, we report a rationally synthesized chalcone-based pyrido[ b ]indole, CPI-7c, as a unique small-molecule inhibitor of MDM2, which not only inhibited MDM2-p53 interaction but also promoted MDM2 degradation. CPI-7c bound to both RING and N-terminal domains of MDM2 to promote its ubiquitin-mediated degradation and p53 stabilization. CPI-7c-induced p53 directly recruited to the promoters of DR4 and DR5 genes and enhanced their expression, resulting in sensitization of TNF-related apoptosis-inducing ligand (TRAIL)-resistant cancer cells toward TRAIL-induced apoptosis. Collectively, we identified CPI-7c as a novel small-molecule inhibitor of MDM2 with a unique two-prong mechanism of action that sensitized TRAIL-resistant cancer cells to apoptosis by modulating the MDM2-p53-DR4/DR5 pathway.
authors.affiliation: Biochemistry Division.
authors.forename: Anup Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry Division and.|Present address: Pennsylvania State University, University Park, PA 16801, USA.
authors.forename: Shikha S
authors.initials: SS
authors.lastname: Chauhan
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow, Uttar Pradesh 226031 , India.
authors.forename: Sudhir Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department of Biophysics, Delhi University , South Campus, New Delhi 110021 , India.
authors.forename: Ved Vrat
authors.initials: VV
authors.lastname: Verma
authors.affiliation: Biochemistry Division.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Singh
authors.affiliation: Biochemistry Division.
authors.forename: Rakesh Kumar
authors.initials: RK
authors.lastname: Arya
authors.affiliation: Biochemistry Division.|Academy of Scientific and Innovative Research, New Delhi 110025, India and.
authors.forename: Shrankhla
authors.initials: S
authors.lastname: Maheshwari
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow, Uttar Pradesh 226031 , India.
authors.forename: Md Sohail
authors.initials: MS
authors.lastname: Akhtar
authors.affiliation: Biochemistry Division.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: Department of Radiation Medicine and Markey Cancer Center, University of Kentucky , Lexington, KY 40536 , USA and.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
authors.affiliation: Medicinal and Process Chemistry Division and.
authors.forename: Prem M S
authors.initials: PMS
authors.lastname: Chauhan
authors.affiliation: Biochemistry Division.|Academy of Scientific and Innovative Research, New Delhi 110025, India and.
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C000622459:1-(3,4-dimethoxyphenyl)-3-(9H-pyrido(3,4-b)indol-1-yl)prop-2-en-1-one; D000970:Antineoplastic Agents; D002243:Carbolines; D011427:Propiophenones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2