The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing
Open accessAbstract
There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix αC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).
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Cites
A quantitative analysis of kinase inhibitor selectivity
Karaman, M. W., Herrgard, S., Treiber, D. K., Gallant, P., Atteridge, C. E., Campbell, B. T., Chan, K. W., Ciceri, P., Davis, M. I., Edeen, P. T., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1358 · Cited by 2,466
Cited by
Duchon, A., & Herault, Y. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00104 · Cited by 181
A quantum mechanics-based halogen bonding scoring function for protein-ligand interactions.
Yang, Z., Liu, Y., Chen, Z., Xu, Z., Shi, J., Chen, K., & Zhu, W. (2015) · Journal of Molecular Modeling · doi:10.1007/s00894-015-2681-6 · Cited by 23
Metadata
- Authors
- Fedorov, O., Huber, K., Eisenreich, A., Filippakopoulos, P., King, O., Bullock, A. N., Szklarczyk, D., Jensen, L. J., Fabbro, D., Trappe, J., Rauch, U., Bracher, F., & Knapp, S.
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 18
- Issue
- 1
- Pages
- 67-76
- ISSN
- 1074-5521 (ISSN-L)
- OpenAlex
- W2170891294
- Cited by
- 204
- References
- 1
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Fedorov, O., Huber, K., Eisenreich, A., Filippakopoulos, P., King, O., Bullock, A. N., Szklarczyk, D., Jensen, L. J., Fabbro, D., Trappe, J., Rauch, U., Bracher, F., & Knapp, S. (2011). Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing. Chemistry & Biology. https://doi.org/10.1016/j.chembiol.2010.11.009
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