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Second-generation CK2α inhibitors targeting the αD pocket

DOI: 10.1039/C7SC05122K DOI Help

Authors: Jessica Iegre (University of Cambridge) , Paul Brear (University of Cambridge) , Claudia De Fusco (University of Cambridge; AstraZeneca) , Masao Yoshida (University of Cambridge; Daiichi Sankyo Co., Ltd.) , Sophie L. Mitchell (University of Cambridge) , Maxim Rossmann (University of Cambridge) , Laura Carro (University of Cambridge) , Hannah F. Sore (University of Cambridge) , Marko Hyvonen (University of Cambridge) , David R. Spring (University of Cambridge)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemical Science , VOL 9 , PAGES 3041 - 3049

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 9537 , 9007

Open Access Open Access

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, 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 (IC50 = 7 μM, GI50 = 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 (IC50) and the ability to inhibit cell proliferation (GI50).

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 22/03/2018 12:01


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)