2. Academic Validation
  3. Exploiting the Cryptic αD Pocket of Casein Kinase 2α (CK2α) to Deliver Highly Potent and Selective Type 1 Inhibitors

Exploiting the Cryptic αD Pocket of Casein Kinase 2α (CK2α) to Deliver Highly Potent and Selective Type 1 Inhibitors

  • J Med Chem. 2025 Oct 23;68(20):21587-21614. doi: 10.1021/acs.jmedchem.5c01807.
Paul A Glossop 1,  Paul Brear 2,  Susanne Wright 3,  Neil Flanagan 3,  Melanie S Glossop 3,  Charlotte A L Lane 3,  Richard P Butt 3,  David R Spring 4,  Marko Hyvönen 2,  Darren Cawkill 3
Affiliations

Affiliations

  • 1 Sandexis Medicinal Chemistry Ltd, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9FF, U.K.
  • 2 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
  • 3 Apollo Therapeutics Ltd, 50-60 Station Road, Cambridge CB1 2JH, U.K.
  • 4 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
PMID: 41085029 DOI: 10.1021/acs.jmedchem.5c01807
Abstract

Casein Kinase 2α (CK2α) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2α has a unique cryptic binding site, the αD pocket, that offers the potential for inhibitors with improved kinase selectivity. The prototype bivalent molecule CAM4066 (6) confirmed that improved selectivity could be achieved while binding in both the ATP-binding site and the αD pocket. A drug discovery project to develop a new series of bivalent CK2α inhibitors with increased cell potency and selectivity identified 61f (APL-5125), a highly potent, ATP-competitive CK2α inhibitor with exquisite kinase selectivity and cellular potency. Compound 61f demonstrates in vivo inhibition of p-AKT S129 in tumors (HCT116) following once-daily oral administration and shows a clear PK-PD relationship with unbound drug exposure. 61f has a superior preclinical profile to existing CK2α inhibitors and is currently under evaluation in patients with advanced solid tumors.

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