Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5

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Välimäki , M J , Tölli , M A , Kinnunen , S M , Aro , J , Serpi , R , Pohjolainen , L , Talman , V , Poso , A & Ruskoaho , H J 2017 , ' Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5 ' , Journal of Medicinal Chemistry , vol. 60 , no. 18 , pp. 7781-7798 . https://doi.org/10.1021/acs.jmedchem.7b00816

Title: Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5
Author: Välimäki, Mika J.; Tölli, Maria A.; Kinnunen, Sini M.; Aro, Jani; Serpi, Raisa; Pohjolainen, Lotta; Talman, Virpi; Poso, Antti; Ruskoaho, Heikki J.
Contributor organization: Faculty of Pharmacy
Division of Pharmacology and Pharmacotherapy
University of Helsinki
Regenerative pharmacology group
Drug Research Program
Date: 2017-09-28
Language: eng
Number of pages: 18
Belongs to series: Journal of Medicinal Chemistry
ISSN: 0022-2623
DOI: https://doi.org/10.1021/acs.jmedchem.7b00816
URI: http://hdl.handle.net/10138/301187
Abstract: 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 mu M), 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.
Subject: BRAIN NATRIURETIC PEPTIDE
HEAVY-CHAIN GENE
STEM-CELLS
HEART REGENERATION
ADULT HEART
EXPRESSION
BINDING
DISEASE
REPAIR
CARDIOGENESIS
TRANSCRIPTION FACTOR
PROTEIN-PROTEIN INTERACTIONS
HYPERTROPHY
DRUG DISCOVERY
317 Pharmacy
Peer reviewed: Yes
Rights: other
Usage restriction: openAccess
Self-archived version: publishedVersion


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