Crystal structure of the Rho-associated coiled-coil kinase 2 inhibitor belumosudil bound to CK2α

Paul Brear and Marko Hyvönen

Acta Crystallographica section F 78: 348-353 (2022)
DOI: 10.1107/S2053230X22008767

PDB coordinates:
7z39 (3D view)


The small molecule belumosudil was initially identified as a selective inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) and has recently been approved for the treatment of graft-versus-host disease. However, recent studies have shown that many of the phenotypes displayed upon treatment with belumosudil were due to CK2α inhibition. CK2α is in itself a very promising therapeutic target for a range of conditions and has recently been put forward as a potential treatment for COVID-19. Belumosudil presents a promising starting point for the development of future CK2α inhibitors as it provides a safe, potent and orally bioavailable scaffold. Continue reading →

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A fragment-based approach leading to the discovery of inhibitors of CK2α with a novel mechanism of action

Paul Brear, Claudia De Fusco, Eleanor L. Atkinson, Jessica Iegre, Nicola J. Francis-Newton, Ashok R. Venkitaraman, Marko Hyvönen and David R. Spring

Journal volume: RSC Med. Chem., 2022, Advance Article
DOI: 10.1039/D2MD00161F


CK2 is a ubiquitous protein kinase with an anti-apoptotic role and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is through allosteric inhibition. The recently identified αD site represents a promising binding site for allosteric inhibition of CK2α. The work presented herein describes the development of a series of CK2α allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. Continue reading →

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Paul & co’s work on CK2α inhibition highlighted

Paul & co’s work on CK2α inhibition highlighted

Dan Erlanson has highlighted our project on Ck2α inhibitor development in his Practical Fragments blog  “Fragment Linking to selective Ck2 inhibitor“.

This a project we have done in close collaboration with David Spring’s group at the Department of Chemistry. The story started from a serendipitous observation that a fragment expected to bind on the top of the N-lobe of CK2α, on the interaction site with scaffolding protein Ck2β bound in a number of different sites on the kinase, including in a new pocket close to the ATP binding site of the kinase. This previously unidentified site was observed only thanks to a new crystal form Paul had obtained. In this crystal form, the so-called αD helix was mobile enough to be displaced by a fragment that, soaked at high concentration,  found a new home in the very hydrophobic pocket that the displacement of the helix revealed. After some optimisation of the fragment and a crystallographic screen to identify ATP-site binding “war heads”, Claudia and others in the Spring lab were able to create the linked molecule CAM4066.

The main story was published in Chemical Science and the detailed description of the design process came out this year in Bioorganic and Medicinal Chemistry.

If interested more in this story, do check in Youtube some of the movies Paul has made from this project:

Development of CAM4066

Optimisation of the fragment in the aD pocket

Growth of the linker from the aD site to the active site

And it should not go forgotten that all the work has been guided continuous crystallographic assessement of the process, with ~30 unique crystal structures in the two papers: 5CVH (3D view), 5CVG (3D view), 5CVF (3D view), 5CU3 (3D view), 5CU4 (3D view), 5CU6 (3D view), 5CSH (3D view), 5CSP (3D view), 5CSV (3D view), 5CSH (3D view), 5CS6 (3D view), 5CLP (3D view), 5MMF (3D view ), 5MMR (3D view ), 5MO5 (3D view ), 5MO6 (3D view ), 5MO7 (3D view ), 5MO8 (3D view ), 5MOD (3D view ), 5MOE (3D view ), 5MOH (3D view ), 5MOT (3D view ), 5MOV (3D view ), 5MOW (3D view ), 5CU0 (3D view ), 5CU2 (3D view ), 5CT0 (3D view ), 5CTP (3D view ), 5CX9 (3D view ).

And there is more to come! Keep your eyes open.

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