Synthesis, Identification, and Structure–Activity Relationship Analysis of GATA4 and NKX2-5 Protein–Protein Interaction Modulators
| Autor: | Heikki Ruskoaho, Mika J. Välimäki, Samuli Auno, Jari Yli-Kauhaluoma, Ingo B. Aumüller, Virpi Talman, Henri Xhaard, Gustav Boije af Gennäs, Sini Kinnunen, Tanja Bruun, Mikael Jumppanen |
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| Přispěvatelé: | Pharmaceutical Design and Discovery group, Division of Pharmaceutical Chemistry and Technology, Drug Research Program, Regenerative pharmacology group, Division of Pharmacology and Pharmacotherapy, Computational Adme, Henri Xhaard / Principal Investigator, Division of Pharmaceutical Biosciences, Jari Yli-Kauhaluoma / Principal Investigator, University Management, Regenerative cardiac pharmacology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
FIBROBLASTS
endocrine system medicine.drug_class Cell Survival 116 Chemical sciences REQUIREMENT Carboxamide SMALL MOLECULES 01 natural sciences Article Protein–protein interaction 03 medical and health sciences Structure-Activity Relationship Drug Discovery Chlorocebus aethiops medicine Structure–activity relationship Animals Viability assay Rats Wistar Transcription factor Cells Cultured 030304 developmental biology 0303 health sciences COS cells Dose-Response Relationship Drug Molecular Structure GATA4 Chemistry MUTATIONS DEFECTS Isoxazoles respiratory system Small molecule 0104 chemical sciences Cell biology GATA4 Transcription Factor Rats 010404 medicinal & biomolecular chemistry TRANSCRIPTION FACTORS 317 Pharmacy DISCOVERY embryonic structures COS Cells cardiovascular system Homeobox Protein Nkx-2.5 Molecular Medicine Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it. |
| Databáze: | OpenAIRE |
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