5CS6

Crystal Structure of CK2alpha with Compound 3 bound

Summary for 5CS6

• Entry DOI: 10.2210/pdb5cs6/pdb
• Descriptor: Casein kinase II subunit alpha, ACETATE ION, 1-(3-chloro-4-propoxyphenyl)methanamine, ... (5 entities in total)
• Functional Keywords: transferase, ck2alpha, ck2a, fragment based drug discovery, high concentration screening, selective atp competitive inhibitors, surface entrophy reduction
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P68400
• Total number of polymer chains: 2
• Total formula weight: 84065.44

Authors

Brear, P.,De Fusco, C.,Georgiou, K.H.,Spring, D.,Hyvonen, M. (deposition date: 2015-07-23, release date: 2016-07-27, Last modification date: 2024-01-10)

Primary citation

Brear, P.,De Fusco, C.,Hadje Georgiou, K.,Francis-Newton, N.J.,Stubbs, C.J.,Sore, H.F.,Venkitaraman, A.R.,Abell, C.,Spring, D.R.,Hyvonen, M.
Specific inhibition of CK2 alpha from an anchor outside the active site.
Chem Sci, 7:6839-6845, 2016

PubMed 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 a of 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 CK2α a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.

PubMed: 28451126
DOI: 10.1039/c6sc02335e

Experimental method

X-RAY DIFFRACTION (1.88 Å)