Second-generation CK2α inhibitors targeting the αD pocket

Abstract

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, <b>CAM4066</b>. Whilst <b>CAM4066</b> 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 <b>CAM4712</b> (IC₅₀ = 7 μM, GI₅₀ = 10.0 ± 3.6 μM), has numerous advantages over the previously reported <b>CAM4066</b>, 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 <b>CAM4066</b>, there was no need to facilitate cellular uptake by making a prodrug. Moreover, <b>CAM4712</b> displayed no drop off between its ability to inhibit the kinase <i>in vitro</i> (IC₅₀) and the ability to inhibit cell proliferation (GI₅₀).