Sammanfattning

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.

Originalspråkengelska
TidskriftJournal of Medicinal Chemistry
Volym62
Utgåva17
Sidor (från-till)8284-8310
Antal sidor27
ISSN0022-2623
DOI
StatusPublicerad - 12 sep 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 317 Farmaci
  • 116 Kemi

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@article{22b82d5c0d8742cf88323c58d9587af8,
title = "Synthesis, identification and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators",
abstract = "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.",
keywords = "DEFECTS, DISCOVERY, FIBROBLASTS, MUTATIONS, REQUIREMENT, SMALL MOLECULES, TRANSCRIPTION FACTORS, 317 Pharmacy, 116 Chemical sciences",
author = "Jumppanen, {Antti Mikael} and Kinnunen, {Sini M.} and V{\"a}lim{\"a}ki, {Mika Juhani} and Virpi Talman and Samuli Auno and Tanja Bruun and {Boije af Genn{\"a}s}, Gustav and Xhaard, {Henri Guillaume Michel} and Aumuller, {Ingo Bernhard} and Heikki Ruskoaho and Jari Yli-Kauhaluoma",
year = "2019",
month = "9",
day = "12",
doi = "10.1021/acs.jmedchem.9b01086",
language = "English",
volume = "62",
pages = "8284--8310",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Synthesis, identification and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators

AU - Jumppanen, Antti Mikael

AU - Kinnunen, Sini M.

AU - Välimäki, Mika Juhani

AU - Talman, Virpi

AU - Auno, Samuli

AU - Bruun, Tanja

AU - Boije af Gennäs, Gustav

AU - Xhaard, Henri Guillaume Michel

AU - Aumuller, Ingo Bernhard

AU - Ruskoaho, Heikki

AU - Yli-Kauhaluoma, Jari

PY - 2019/9/12

Y1 - 2019/9/12

N2 - 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.

AB - 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.

KW - DEFECTS

KW - DISCOVERY

KW - FIBROBLASTS

KW - MUTATIONS

KW - REQUIREMENT

KW - SMALL MOLECULES

KW - TRANSCRIPTION FACTORS

KW - 317 Pharmacy

KW - 116 Chemical sciences

U2 - 10.1021/acs.jmedchem.9b01086

DO - 10.1021/acs.jmedchem.9b01086

M3 - Article

VL - 62

SP - 8284

EP - 8310

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -