Second-generation CK2 alpha inhibitors targeting the alpha D pocket

• Published in: Chemical science (Cambridge) Vol. 9; no. 11; pp. 3041 - 3049
• Main Authors: Iegre, Jessica, Brear, Paul, De Fusco, Claudia, Yoshida, Masao, Mitchell, Sophie L., Rossmann, Maxim, Carro, Laura, Sore, Hannah F., Hyvonen, Marko, Spring, David R.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 21.03.2018; Royal Society of Chemistry
• Subjects: Binding sites; Business competition; Cell cycle; Chemistry; Chemistry, Multidisciplinary; Inhibitors; Kinases; Physical Sciences; Science & Technology; RESISTANCE; SITE; SELECTIVE INHIBITOR; CANCER; PROTEIN-KINASE CK2; DRUG DISCOVERY
• 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 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)).