Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer

Anup Kumar Singh; Shikha S Chauhan; Sudhir Kumar Singh; Ved Vrat Verma; Akhilesh Singh; Rakesh Kumar Arya; Shrankhla Maheshwari; Md Sohail Akhtar; Jayanta Sarkar; Vivek M Rangnekar; Prem M S Chauhan; Dipak Datta

doi:10.1093/carcin/bgw088

Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer

Carcinogenesis. 2016 Nov 1;37(11):1027-1040. doi: 10.1093/carcin/bgw088.

Authors

Affiliations

¹ Biochemistry Division.
² Medicinal and Process Chemistry Division and.
³ Present address: Pennsylvania State University, University Park, PA 16801, USA.
⁴ Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow, Uttar Pradesh 226031 , India.
⁵ Department of Biophysics, Delhi University , South Campus, New Delhi 110021 , India.
⁶ Academy of Scientific and Innovative Research, New Delhi 110025, India and.
⁷ Department of Radiation Medicine and Markey Cancer Center, University of Kentucky , Lexington, KY 40536 , USA and.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carbolines / chemistry
Carbolines / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm*
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Targeted Therapy
Promoter Regions, Genetic
Propiophenones / chemistry
Propiophenones / pharmacology*
Protein Binding
Protein Stability
Proteolysis
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / chemistry
Proto-Oncogene Proteins c-mdm2 / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Transcription, Genetic / drug effects
Tumor Suppressor Protein p53 / metabolism
Ubiquitination / drug effects
Up-Regulation

Substances

1-(3,4-dimethoxyphenyl)-3-(9H-pyrido(3,4-b)indol-1-yl)prop-2-en-1-one
Antineoplastic Agents
Carbolines
Propiophenones
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
TNFRSF10A protein, human
TNFRSF10B protein, human
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2

Abstract

Publication types

MeSH terms

Substances

Grants and funding