期刊
CHEMICAL SCIENCE
卷 9, 期 11, 页码 3041-3049出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7sc05122k
关键词
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资金
- European Research Council under the European Union's Seventh Framework Programme (FP7)/ERC [279337/DOS]
- Wellcome Trust [090340/Z/09/Z, 107714/Z/15/Z]
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Royal Society
- Herchel Smith Funds
- Trinity College, University of Cambridge
- CASE-EPSRC award
- Wellcome Trust [107714/Z/15/Z] Funding Source: Wellcome Trust
- EPSRC [EP/P020291/1, EP/J016012/1] Funding Source: UKRI
CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, CAM4066. Whilst CAM4066 bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2 alpha inhibitor that binds completely outside the active site. This second generation alpha D-site binding inhibitor, compound CAM4712 (IC50 = 7 mu M, GI(50) = 10.0 +/- 3.6 mu M), has numerous advantages over the previously reported CAM4066, including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with CAM4066, there was no need to facilitate cellular uptake by making a prodrug. Moreover, CAM4712 displayed no drop off between its ability to inhibit the kinase in vitro (IC50) and the ability to inhibit cell proliferation (GI(50)).
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