Specific inhibition of CK2α from an anchor outside the active site

Abstract

CAM4066, a specific CK2α kinase inhibitor, is anchored in the cryptic αD pocket outside the active site and inserts a “warhead” into the active site, blocking ATP binding and thereby inhibiting the kinase.

Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

“…In that respect, small probe molecules such as ethylene glycol and propylene glycol, which in the present work are shown to discover cryptic sites in proteins mainly by inducing side chain movements, can be used to probe the vicinity of functional sites of pharmaceutically important protein targets for potential cryptic sites and therefore can further the drug-design process for those targets. In fact, upon screening protein CK2 α , a Ser/Thr kinase and an important target in cancer therapy, with fragment library, a fragment 3,4 dichlorophenethylamine identified a cryptic pocket, termed as “ α D pocket”, adjacent to ATP binding site by displacing Tyr125 (PDB ID 5CLP) [41]. This cryptic site was then used to develop a new CK2 α inhibitor with high nanomolar affinity [41].…”

“…In fact, upon screening protein CK2 α , a Ser/Thr kinase and an important target in cancer therapy, with fragment library, a fragment 3,4 dichlorophenethylamine identified a cryptic pocket, termed as “ α D pocket”, adjacent to ATP binding site by displacing Tyr125 (PDB ID 5CLP) [41]. This cryptic site was then used to develop a new CK2 α inhibitor with high nanomolar affinity [41]. Interestingly, in one structure of CK2 α (PDB ID 3WAR), it was observed that two ethylene glycol molecules were bound at the entrance of the partially opened α D pocket [41, 42] further supporting our concept of using small glycols to identify cryptic sites in protein targets leaving to the use the identified cryptic sites for drug-design purposes.…”

“…This cryptic site was then used to develop a new CK2 α inhibitor with high nanomolar affinity [41]. Interestingly, in one structure of CK2 α (PDB ID 3WAR), it was observed that two ethylene glycol molecules were bound at the entrance of the partially opened α D pocket [41, 42] further supporting our concept of using small glycols to identify cryptic sites in protein targets leaving to the use the identified cryptic sites for drug-design purposes. Another crystallography study of protein CK2 α [42] has shown several ethylene glycol molecules occupying physiologically significant sites of CK2 α suggesting their use in computational methods for binding site determination.…”

Optimization of pyrazolo[1,5-a]pyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor

“…Main off-targets of silmitasertib (1) reported to have antiproliferative effects are for example the cyclin-dependent kinase (CDK1) [43,44], PIM-1 protooncogene, serine/threonine kinase (PIM1) [45], Homeodomain-interacting protein kinase 3 (HIPK3) [46,47], TANK-binding kinase 1 (TBK1) [48] or FMS-like tyrosine kinase 3 (FLT3) [49,50]. More recently some more selective CK2 inhibitors have been reported, including GO289 by Oshima et al [51] or an allosteric inhibitor CAM4066 by Brear et al [18]. However, the allosteric inhibitors are still weak and would require optimization and the selectivity of GO289 has not been comprehensively assessed.…”

Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition

“…Currently, only one molecule (CX‐4945), showing high specificity, has reached the clinical stages . Recently, novel molecules and fragments have been discovered that target either the CK2α‐β interface, or other sites in conjunction with the active site …”