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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23
Soo-Yeon Hwang1, Kyung-Hwa Jeon1, Hwa-Jong Lee1
1College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
Abstract:
HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success; however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab. In this study, we synthesized a total of 26 compounds consisting of 10 chalcones, 7 pyrazoline acetyl, and 9 pyrazoline propionyl derivatives, and evaluated their biological activity as potential ELF3-MED23 PPI inhibitors. Upon systematic analysis, candidate compound 10 was selected due to its potency in downregulating reporter gene activity of ERBB2 promoter confirmed by SEAP activity and its effect on HER2 protein and mRNA levels. Compound 10 effectively disrupted the binding interface between the ELF3 TAD domain and the 391-582 amino acid region of MED23, resulting in successful inhibition of the ELF3-MED23 PPI. This intervention led to a substantial reduction in HER2 levels and its downstream signals in the HER2-positive gastric cancer cell line. Subsequently, compound 10 induced significant apoptosis and anti-proliferative effects, demonstrating superior in vitro and in vivo anticancer activity overall. We found that the anticancer activity of compound 10 was not only restricted to trastuzumab-sensitive cases, but was also valid for trastuzumab-refractory clones. This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.
Insights
A new compound, designated compound 10, effectively inhibits the ELF3-MED23 protein-protein interaction, reducing HER2 levels in gastric cancer. This novel agent shows promise against both trastuzumab-sensitive and resistant HER2-overexpressing cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- HER2 overexpression drives aggressive solid tumors, particularly gastric cancers.
- Trastuzumab is a successful HER2-targeted therapy, but drug resistance is a significant clinical challenge.
- Targeting protein-protein interactions (PPIs) offers an alternative therapeutic strategy for HER2-overexpressing cancers.
Purpose of the Study:
- To identify novel inhibitors of the ELF3-MED23 protein-protein interaction as a therapeutic approach for HER2-overexpressing cancers.
- To evaluate the anticancer activity of synthesized compounds, focusing on their ability to disrupt the ELF3-MED23 PPI.
- To assess the efficacy of the lead compound against trastuzumab-sensitive and resistant gastric cancer models.
Main Methods:
- Synthesis and biological evaluation of 26 compounds (chalcones, pyrazoline acetyl, and pyrazoline propionyl derivatives) as ELF3-MED23 PPI inhibitors.
- Assay of reporter gene activity (SEAP) to confirm downregulation of the ERBB2 promoter.
- Assessment of compound effects on HER2 protein and mRNA levels, ELF3-MED23 binding interface disruption, and downstream signaling.
- In vitro and in vivo evaluation of anticancer effects, including apoptosis and anti-proliferative activity.
Main Results:
- Compound 10 demonstrated potent inhibition of ELF3-MED23 PPI by disrupting the binding interface between ELF3 TAD and MED23 (391-582 aa).
- Compound 10 significantly reduced HER2 levels and downstream signaling in HER2-positive gastric cancer cells.
- The compound induced substantial apoptosis and anti-proliferative effects, exhibiting superior in vitro and in vivo anticancer activity.
- Compound 10 effectively inhibited both trastuzumab-sensitive and trastuzumab-refractory gastric cancer cells.
Conclusions:
- Compound 10 is a novel ELF3-MED23 PPI inhibitor with significant anticancer activity against HER2-overexpressing gastric cancers.
- This compound effectively reduces HER2 levels and overcomes trastuzumab resistance.
- Compound 10 represents a promising therapeutic strategy for HER2-positive and trastuzumab-refractory gastric cancers.
