Synthesis and biological evaluation of dual MDM2/XIAP inhibitors based on the tetrahydroquinoline scaffold
Najah Albadari1, Yang Xie1, Tao Liu2
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States.
Abstract:
Overexpression of both human murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP) is detected in tumor cells from several cancer types, including childhood acute leukemia lymphoma (ALL), neuroblastoma (NB), and prostate cancer, and is associated with disease progression and treatment resistance. In this report, we described the design and syntheses of a series of dual MDM2/XIAP inhibitors based on the tetrahydroquinoline scaffold from our previously reported lead compound JW-2-107 and tested their cytotoxicity in a panel of human cancer cell lines. The best compound identified in this study is compound 3e. Western blot analyses demonstrated that treatments with 3e decreased MDM2 and XIAP protein levels and increased expression of p53, resulting in cancer cell growth inhibition and cell death. Furthermore, compound 3e effectively inhibited tumor growth in vivo when tested using a human 22Rv1 prostate cancer xenograft model. Collectively, results in this study strongly suggest that the tetrahydroquinoline scaffold, represented by 3e and our earlier lead compound JW-2-107, has abilities to dual target MDM2 and XIAP and is promising for further preclinical development.
Insights
This study developed novel dual inhibitors targeting human murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP). Compound 3e demonstrated significant cancer cell growth inhibition and tumor reduction in preclinical models.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Overexpression of MDM2 and XIAP is common in various cancers, correlating with disease progression and treatment resistance.
- Targeting both MDM2 and XIAP offers a potential strategy to overcome therapeutic challenges in cancer treatment.
Purpose of the Study:
- To design and synthesize novel dual inhibitors of MDM2 and XIAP based on a tetrahydroquinoline scaffold.
- To evaluate the efficacy of these compounds in inhibiting cancer cell growth and tumor progression.
Main Methods:
- Synthesis of a series of tetrahydroquinoline-based compounds.
- Cytotoxicity assays in human cancer cell lines.
- Western blot analysis to assess protein level changes (MDM2, XIAP, p53).
- In vivo efficacy study using a prostate cancer xenograft model.
Main Results:
- Compound 3e emerged as the most potent dual MDM2/XIAP inhibitor.
- Treatment with 3e reduced MDM2 and XIAP protein levels and increased p53 expression.
- 3e demonstrated significant inhibition of cancer cell growth and induced cell death.
- In vivo studies showed that 3e effectively inhibited tumor growth in a prostate cancer xenograft model.
Conclusions:
- The tetrahydroquinoline scaffold is a promising basis for developing dual MDM2/XIAP inhibitors.
- Compound 3e shows significant potential for further preclinical development as an anti-cancer therapeutic.
