Interrupting specific hydrogen bonds between ELF3 and MED23 as an alternative drug resistance-free strategy for HER2-overexpressing cancers

Hwang, Soo‐Yeon; Park, Seojeong; Jo, Hye-Jin; Seo, Seung Hee; Jeon, Kyung-Hwa; Kim, Seojeong; Jung, Ah-Reum; Song, Chanju; Ahn, Myoung Hwan; Kwak, Soo Yeon; Lee, Hwa-Jong; Uesugi, Motonari; Na, Younghwa; Kwon, Youngjoo

doi:10.1016/j.jare.2022.08.003

Cited by 6 publications

(15 citation statements)

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“…As HER2 targeting primarily involves the already overexpressed HER2 and its downstream signaling pathways, typically driven by the gene amplification [42], alternative approaches have been explored to downregulate HER2 signaling from the gene expression level. Specifically, strategies have been investigated to inhibit the interaction between transcription factor (TF), ELF3, and its coactivator, MED23 [29,30,[43][44][45]. ELF3, a critical regulator of HER2 gene expression, acts on the ETS transcriptional response element of HER2 promoter and interacts with MED23 to promote HER2 overexpression [19,46].…”

Section: Discussionmentioning

confidence: 99%

“…However, one of the significant drawback of this drug is the development of resistance, which readily occurs within 1 year of medication [36]. In our previous study, we demonstrated that inhibiting the ELF3-MED23 PPI to downregulate HER2 at the transcriptional level could serve as a potentially promising alternative therapeutic option to trastuzumab [29]. Consequently, we sought to determine whether compound 10 holds the capability to overcome trastuzumab resistance.…”

Section: Compound 10 As a Novel Strategy To Overcome Trastuzumab Resi...mentioning

confidence: 99%

“…SEAP assay was performed as described previously [29]. The mammalian expression vector, pBJ-GAL4-ELF3 was co-transfected with the reporter gene, pG5IL2SX to 293T human kidney cells.…”

Section: Secreted Alkaline Phosphatase (Seap) Assaymentioning

confidence: 99%

“…FP assay was conducted following a previously described method [29]. Different concentrations of (His) 6 -MED23 391-582 and 10 nM of FITC-labeled ELF3 129-145 peptide were combinded in assay buffer to determine the K d value in advance.…”

Section: Fluorescence Poliarization (Fp) Assaymentioning

confidence: 99%

“…5 μM of compound 10 was co-applied to the system. Cell lysis was prepared under the same procedure as for the western blot analyses [29]. 1000 μg of cell lysates were incubated overnight with Glutathione Sepharose™ beads (GE Healthcare, UK) at 4 °C on a rotator.…”

Section: Glutathione S-transferase (Gst) Pull-down Assaymentioning

confidence: 99%

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Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as Novel Inhibitor for ELF3-MED23 Interaction

Hwang,

Jeon,

Lee

et al. 2024

Preprint

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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 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 superiorin vitroandin vivoanticancer 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.

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Section: Discussionmentioning

confidence: 99%

Section: Compound 10 As a Novel Strategy To Overcome Trastuzumab Resi...mentioning

confidence: 99%

“…SEAP assay was performed as described previously [29]. The mammalian expression vector, pBJ-GAL4-ELF3 was co-transfected with the reporter gene, pG5IL2SX to 293T human kidney cells.…”

Section: Secreted Alkaline Phosphatase (Seap) Assaymentioning

confidence: 99%

Section: Fluorescence Poliarization (Fp) Assaymentioning

confidence: 99%

Section: Glutathione S-transferase (Gst) Pull-down Assaymentioning

confidence: 99%

See 3 more Smart Citations