Exploiting the Cryptic αD Pocket of Casein Kinase 2α (CK2α) to Deliver Highly Potent and Selective Type 1 Inhibitors
Paul A Glossop1, Paul Brear2, Susanne Wright3
1Sandexis Medicinal Chemistry Ltd, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9FF, U.K.
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.
Insights
Researchers developed a novel bivalent inhibitor targeting casein kinase 2α (CK2α), a key protein in cancer. The new compound, 61f, shows high selectivity and potency, inhibiting tumor growth in preclinical studies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Casein kinase 2α (CK2α) is implicated in tumorigenic signaling pathways.
- CK2α possesses a unique cryptic binding site (αD pocket) for selective inhibition.
- Previous work demonstrated bivalent molecule CAM4066 achieved selectivity targeting the ATP-binding site and αD pocket.
Purpose of the Study:
- To develop novel bivalent CK2α inhibitors with enhanced cell potency and selectivity.
- To identify a lead compound with superior preclinical properties for oncology applications.
Main Methods:
- Drug discovery project focused on bivalent CK2α inhibitors.
- Synthesis and evaluation of novel chemical entities.
- In vitro kinase selectivity assays and cellular potency assessments.
- In vivo pharmacokinetic-pharmacodynamic (PK-PD) studies in tumor models.
Main Results:
- Identified compound 61f (APL-5125) as a potent, ATP-competitive CK2α inhibitor.
- 61f demonstrated exquisite kinase selectivity and high cellular potency.
- In vivo studies showed 61f inhibited p-AKT S129 in HCT116 tumors after oral administration.
- A clear PK-PD relationship was established for 61f.
Conclusions:
- Compound 61f exhibits a superior preclinical profile compared to existing CK2α inhibitors.
- 61f represents a promising therapeutic candidate for advanced solid tumors.
- The compound is currently undergoing clinical evaluation in patients.
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