Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/97051 |
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| author | Soo-Yeon Hwang Kyung-Hwa Jeon Hwa-Jong Lee Inhye Moon Sehyun Jung Seul-Ah Kim Hyunji Jo Seojeong Park Misun Ahn Soo-Yeon Kwak Younghwa Na Youngjoo Kwon |
| author_facet | Soo-Yeon Hwang Kyung-Hwa Jeon Hwa-Jong Lee Inhye Moon Sehyun Jung Seul-Ah Kim Hyunji Jo Seojeong Park Misun Ahn Soo-Yeon Kwak Younghwa Na Youngjoo Kwon |
| author_sort | Soo-Yeon Hwang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-299cfce3e3f844a5afe06b7ebbe171b3 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-299cfce3e3f844a5afe06b7ebbe171b32024-12-07T02:04:22ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.97051Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interactionSoo-Yeon Hwang0Kyung-Hwa Jeon1Hwa-Jong Lee2Inhye Moon3Sehyun Jung4Seul-Ah Kim5Hyunji Jo6Seojeong Park7Misun Ahn8Soo-Yeon Kwak9Younghwa Na10Youngjoo Kwon11https://orcid.org/0000-0001-6256-3042College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaCollege of Pharmacy, CHA University, Pocheon, Republic of KoreaCollege of Pharmacy, CHA University, Pocheon, Republic of KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of KoreaHER2 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.https://elifesciences.org/articles/97051HER2-overexpressing cancersgastric cancertrastuzumab-resistanceprotein-protein interaction inhibitor4-Methoxy-3-((3-methylbut-2-en-1-yl)oxy)benzaldehyde |
| spellingShingle | Soo-Yeon Hwang Kyung-Hwa Jeon Hwa-Jong Lee Inhye Moon Sehyun Jung Seul-Ah Kim Hyunji Jo Seojeong Park Misun Ahn Soo-Yeon Kwak Younghwa Na Youngjoo Kwon Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction eLife HER2-overexpressing cancers gastric cancer trastuzumab-resistance protein-protein interaction inhibitor 4-Methoxy-3-((3-methylbut-2-en-1-yl)oxy)benzaldehyde |
| title | Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction |
| title_full | Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction |
| title_fullStr | Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction |
| title_full_unstemmed | Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction |
| title_short | Synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for ELF3-MED23 interaction |
| title_sort | synthesis and biological assessment of chalcone and pyrazoline derivatives as novel inhibitor for elf3 med23 interaction |
| topic | HER2-overexpressing cancers gastric cancer trastuzumab-resistance protein-protein interaction inhibitor 4-Methoxy-3-((3-methylbut-2-en-1-yl)oxy)benzaldehyde |
| url | https://elifesciences.org/articles/97051 |
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