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.
| Original language | English |
|---|---|
| Journal | Journal of Medicinal Chemistry |
| Volume | 62 |
| Issue number | 17 |
| Pages (from-to) | 8284-8310 |
| Number of pages | 27 |
| ISSN | 0022-2623 |
| DOIs | |
| Publication status | Published - 12 Sep 2019 |
| MoE publication type | A1 Journal article-refereed |
Fields of Science
- DEFECTS
- DISCOVERY
- FIBROBLASTS
- MUTATIONS
- REQUIREMENT
- SMALL MOLECULES
- TRANSCRIPTION FACTORS
- 317 Pharmacy
- 116 Chemical sciences
Cite this
}
Synthesis, identification and structure-activity relationship analysis of GATA4 and NKX2-5 protein-protein interaction modulators. / Jumppanen, Antti Mikael; Kinnunen, Sini M.; Välimäki, Mika Juhani; Talman, Virpi; Auno, Samuli; Bruun, Tanja; Boije af Gennäs, Gustav; Xhaard, Henri Guillaume Michel; Aumuller, Ingo Bernhard; Ruskoaho, Heikki ; Yli-Kauhaluoma, Jari .
In: Journal of Medicinal Chemistry, Vol. 62, No. 17, 12.09.2019, p. 8284-8310.Research output: Contribution to journal › Article › Scientific › peer-review
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 -