Crystal structure of the Rho‐associated coiled‐coil kinase 2 inhibitor belumosudil bound to CK2α. Issue 10 (26th September 2022)

• Record Type: Journal Article
• Authors: Brear, Paul; Hyvönen, Marko
• Is Part Of: Acta crystallographica. Volume 78:Issue 10(2022)
• Page Start: 348
• Page End: 353
• Publication Date: 2022-09-26
• Subjects: belumosudil -- CK2α inhibition -- Rho‐associated coiled‐coil kinase 2 -- ROCK2 inhibition -- kinase inhibitors -- selective inhibitors; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X22008767
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : The crystal structure of the Rho‐associated coiled‐coil kinase 2 (ROCK2) inhibitor belumosudil bound to CK2α suggests ways in which specificity for either ROCK2 or CK2α can be increased. Abstract : 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. Therefore, several of the major hurdles in drug development have already been overcome. Here, the crystal structure of belumosudil bound to the ATP site of CK2α is presented. This crystal structure combined with modelling studies further elucidates how belumosudil could be developed into a selective and potent CK2α or ROCK2 inhibitor.