Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. / Fedorov, Oleg; Huber, Kilian; Eisenreich, Andreas; Filippakopoulos, Panagis; King, Oliver; Bullock, Alex N; Szklarczyk, Damian; Jensen, Lars J; Fabbro, Doriano; Trappe, Jörg; Rauch, Ursula; Bracher, Franz; Knapp, Stefan.

In: Chemistry & Biology, Vol. 18, No. 1, 2011, p. 67-76.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Fedorov, O, Huber, K, Eisenreich, A, Filippakopoulos, P, King, O, Bullock, AN, Szklarczyk, D, Jensen, LJ, 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, vol. 18, no. 1, pp. 67-76. https://doi.org/10.1016/j.chembiol.2010.11.009

APA

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, 18(1), 67-76. https://doi.org/10.1016/j.chembiol.2010.11.009

Vancouver

Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, Bullock AN et al. Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chemistry & Biology. 2011;18(1):67-76. https://doi.org/10.1016/j.chembiol.2010.11.009

Author

Fedorov, Oleg ; Huber, Kilian ; Eisenreich, Andreas ; Filippakopoulos, Panagis ; King, Oliver ; Bullock, Alex N ; Szklarczyk, Damian ; Jensen, Lars J ; Fabbro, Doriano ; Trappe, Jörg ; Rauch, Ursula ; Bracher, Franz ; Knapp, Stefan. / Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. In: Chemistry & Biology. 2011 ; Vol. 18, No. 1. pp. 67-76.

Bibtex

@article{24d73f2b0f654d9fb2cc629c487c211d,
title = "Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing",
abstract = "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 aC 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).",
keywords = "Alternative Splicing, Catalytic Domain, Endothelial Cells, Heterocyclic Compounds, 2-Ring, Humans, Models, Molecular, Nitriles, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, RNA, Messenger, RNA-Binding Proteins, Substrate Specificity, Thromboplastin",
author = "Oleg Fedorov and Kilian Huber and Andreas Eisenreich and Panagis Filippakopoulos and Oliver King and Bullock, {Alex N} and Damian Szklarczyk and Jensen, {Lars J} and Doriano Fabbro and J{\"o}rg Trappe and Ursula Rauch and Franz Bracher and Stefan Knapp",
note = "Copyright {\textcopyright} 2011 Elsevier Ltd. All rights reserved.",
year = "2011",
doi = "10.1016/j.chembiol.2010.11.009",
language = "English",
volume = "18",
pages = "67--76",
journal = "Chemistry and Biology",
issn = "2451-9448",
publisher = "Elsevier",
number = "1",

}

RIS

TY - JOUR

T1 - Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

AU - Fedorov, Oleg

AU - Huber, Kilian

AU - Eisenreich, Andreas

AU - Filippakopoulos, Panagis

AU - King, Oliver

AU - Bullock, Alex N

AU - Szklarczyk, Damian

AU - Jensen, Lars J

AU - Fabbro, Doriano

AU - Trappe, Jörg

AU - Rauch, Ursula

AU - Bracher, Franz

AU - Knapp, Stefan

N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.

PY - 2011

Y1 - 2011

N2 - 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 aC 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).

AB - 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 aC 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).

KW - Alternative Splicing

KW - Catalytic Domain

KW - Endothelial Cells

KW - Heterocyclic Compounds, 2-Ring

KW - Humans

KW - Models, Molecular

KW - Nitriles

KW - Phosphorylation

KW - Protein Kinase Inhibitors

KW - Protein-Serine-Threonine Kinases

KW - Protein-Tyrosine Kinases

KW - RNA, Messenger

KW - RNA-Binding Proteins

KW - Substrate Specificity

KW - Thromboplastin

U2 - 10.1016/j.chembiol.2010.11.009

DO - 10.1016/j.chembiol.2010.11.009

M3 - Journal article

C2 - 21276940

VL - 18

SP - 67

EP - 76

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 1

ER -

ID: 40291054