Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 4, Pages 1803-1816Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01766
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Funding
- NIH [GM117424, AI118985, NS102432, R35 HL135737A]
- Deutsche Forschungsgemeinschaft (DFG) [EN381/2-3]
- Region Rhone-Alpes [12-008707-01]
- Canceropole Lyon Rhone-Alpes Auvergne (CLARA) [2011-097]
- [R01 GM071872]
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CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non-ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD NMR, circular dichroism spectroscopy, and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the alpha C helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC50 of 3.4 mu M against purified CK2 alpha in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into anticancer drugs.
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