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CLK2 and CLK4 are regulators of DNA damage-induced NF-κB targeted by novel small molecule inhibitors

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Item Type:Article
Title:CLK2 and CLK4 are regulators of DNA damage-induced NF-κB targeted by novel small molecule inhibitors
Creators Name:Mucka, P. and Lindemann, P. and Bosco, B. and Willenbrock, M. and Radetzki, S. and Neuenschwander, M. and Brischetto, C. and von Kries, J.P. and Nazaré, M. and Scheidereit, C.
Abstract:Transcription factor NF-κB potently activates anti-apoptotic genes, and its inactivation significantly reduces tumor cell survival following genotoxic stresses. We identified two structurally distinct lead compounds that selectively inhibit NF-κB activation by DNA double-strand breaks, but not by other stimuli, such as TNFα. Our compounds do not directly inhibit previously identified regulators of this pathway, most critically including IκB kinase (IKK), but inhibit signal transmission in-between ATM, PARP1, and IKKγ. Deconvolution strategies, including derivatization and in vitro testing in multi-kinase panels, yielded shared targets, cdc-like kinase (CLK) 2 and 4, as essential regulators of DNA damage-induced IKK and NF-κB activity. Both leads sensitize to DNA damaging agents by increasing p53-induced apoptosis, thereby reducing cancer cell viability. We propose that our lead compounds and derivatives can be used in context of genotoxic therapy-induced or ongoing DNA damage to increase tumor cell apoptosis, which may be beneficial in cancer treatment.
Keywords:Cancer Cells, NF-κB, DNA Damage, Small Molecules, Derivatives, Kinase Inhibitors, IκB Kinase, ATM, CLK2, CLK4
Source:Cell Chemical Biology
Publisher:Cell Press
Page Range:1303-1312.e3
Date:19 October 2023
Official Publication:https://doi.org/10.1016/j.chembiol.2023.06.027
PubMed:View item in PubMed

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