University of Oulu

Mika J. Välimäki, Marja A. Tölli, Sini M. Kinnunen, Jani Aro, Raisa Serpi, Lotta Pohjolainen, Virpi Talman, Antti Poso, and Heikki J. Ruskoaho, Journal of Medicinal Chemistry 2017 60 (18), 7781-7798 DOI: 10.1021/acs.jmedchem.7b00816

Discovery of small molecules targeting the synergy of cardiac transcription factors GATA4 and NKX2-5

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Author: Välimäki, Mika J.1,2; Tölli, Marja A.2; Kinnunen, Sini M.1,2;
Organizations: 1Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland
2Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu FI-90014, Finland
3Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, Kuopio FI-70211, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.9 MB)
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Language: English
Published: American Chemical Society, 2017
Publish Date: 2019-07-19


Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4–NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC₅₀ = 3 μM), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 60
Issue: 18
Pages: 7781 - 7798
DOI: 10.1021/acs.jmedchem.7b00816
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
Funding: We thank Marja Arbelius, Kirsi Salo, Nina Sipari, Niklas Johansson, and Gustav Boije af Gennäs for their expert technical assistance. This work was supported by the Finnish Funding Agency for Innovation (Tekes, 3iRegeneration, Project 40395/13), the Academy of Finland (Project 2666621), the Finnish Foundation for Cardiovascular Research, and the Sigrid Jusélius Foundation.
Copyright information: © 2017 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see