PDBsum entry 5csv

Transferase

PDB id: 5csv

Contents

Protein chain

327 a.a.

Ligands

ACT ×2

GAB

Waters ×267

References listed in PDB file

Key reference

• Title: Specific inhibition of ck2α from an anchor outside the active site.
• Authors: P.Brear, C.De fusco, K.Hadje georgiou, N.J.Francis-Newton, C.J.Stubbs, H.F.Sore, A.R.Venkitaraman, C.Abell, D.R.Spring, M.Hyvönen.
• Ref.: Chem Sci, 2016, 7, 6839-6845.
• PubMed id: 28451126

Abstract

The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with aK_dof 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2αviaa novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.