Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling
Abstract
Differentiation of human pluripotent stem cells as embryoid bodies (EBs) has been achieved previously with p38alfa MAPK inhibitors such as SB203580 with moderate efficiency of 10-15%. We synthesized and screened 42 compounds that are 2,4,5-trisubstituted azole analogues of SB203580 for efficient cardiomyocyte differentiation. Our screen identified novel compounds that have similar cardiac differentiation activity as SB203580. However, the cardiac differentiation did not correlate with p38alfa MAPK inhibition, indicating an alternative mechanism in cardiac differentiation. Upon profiling several 2,4,5-trisubstituted azole compounds against a panel of 97 kinases we identified several off targets, among them casein kinases 1 (CK1). The cardiomyogenic activities of SB203580 and its analogues showed a correlation with post mesoderm Wnt/beta-catenin pathway inhibition of CK1 epsilon and delta. These findings united the mechanism of 2,4,5-trisubstituted azole with the current theory of Wnt/beta-catenin regulated pathway of cardiac differentiation. Consequently an efficient cardiomyocyte protocol was developed with Wnt activator CHIR99021 and 2,4,5-trisubstituted azoles to give high yields of 50-70% cardiomyocytes and a 2-fold increase in growth.
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These inhibitors vary in their target specificity, which raises concerns about linkage of target modulation to phenotype.
“These inhibitors vary in their target specificity, which raises concerns about linkage of target modulation to phenotype—a key aspect of drug discovery target validation, as documented previously [34].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [34]
Cites
Comprehensive analysis of kinase inhibitor selectivity
Davis, M. I., Hunt, J. P., Herrgard, S., Ciceri, P., Wodicka, L. M., Pallares, G., Hocker, M., Treiber, D. K., & Zarrinkar, P. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1990 · Cited by 2,409 · see citing works
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Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
Maphis, N., Jiang, S., Xu, G., Kokiko-Cochran, O. N., Roy, S. M., Van Eldik, L. J., Watterson, D. M., Lamb, B. T., & Bhaskar, K. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0221-y · Cited by 144 · see citing works
“, [34, 51]), where each kinase target may have a role that varies quantitatively during the phenotypic change.”
Downregulation of p38 MAPK Signaling Pathway Ameliorates Tissue-Engineered Corneal Epithelium
Mao, Y., Ou, S., Zhu, C., Lin, S., Liu, X., Liang, M., Yu, J., Wu, Y., He, H., Zong, R., et al. (2022) · Tissue Engineering Part A · doi:10.1089/ten.tea.2022.0082 · Cited by 18 · see citing works
Self-citation
- Authors
- Laco, F., Low, J.-L., Seow, J., Woo, T. L., Zhong, Q., Seayad, J., Liu, Z., Wei, H., Reuveny, S., Elliott, D. A., Chai, C. L. L., & Oh, S. K. W.
- Affiliations
- Bioprocessing Technology Institute (SG)
- Institute of Chemical and Engineering Sciences (SG)
- National University of Singapore (SG)
- National Heart Centre Singapore (SG)
- Royal Children's Hospital (AU)
- Corresponding author
- Oh, Steve K.W.
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 80
- Pages
- 56-70
- ISSN
- 0022-2828 (ISSN-L)
- OpenAlex
- W2015966243
- Cited by
- 23
- References
- 1
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 1
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-08-01)
- Open access
- closed
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- A*STAR
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- cardiomyocyte differentiation, pluripotent stem cells, SB203580, casein kinase 1, Wnt/β-catenin signaling, p38 MAPK, CHIR99021, embryoid bodies, kinase profiling, off-target effects
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Humans, Imidazoles, Mesoderm, Pyridines, Drug Design, MAP Kinase Signaling System, Myocytes, Cardiac, Organogenesis, Pluripotent Stem Cells, Casein Kinase I, Protein Kinase Inhibitors, Mice, Wnt Signaling Pathway
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