Second-generation CK2α inhibitors targeting the αD pocketElectronic supplementary information (ESI) available: All experimental details, crystallographic data collection and refinement statistics, details of chemical synthesis, additional figures and tables. See DOI: 10.1039/c7sc05122k

• Main Authors: Iegre, Jessica, Brear, Paul, De Fusco, Claudia, Yoshida, Masao, Mitchell, Sophie L, Rossmann, Maxim, Carro, Laura, Sore, Hannah F, Hyvönen, Marko, Spring, David R
• Format: Journal Article
• Published: 14.03.2018
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c7sc05122k

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 CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound CAM4712 (IC 50 = 7 μM, GI 50 = 10.0 ± 3.6 μM), 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 (IC 50 ) and the ability to inhibit cell proliferation (GI 50 ). We describe the development of a CAM4712 , a novel CK2α inhibitor which does not interact with the ATP binding site and shows improved properties over the first-generation inhibitor CAM4066 .