9qy7 | pdb_00009qy7
Crystal Structure of 54e bound to CK2a
Structural highlights
FunctionCSK21_HUMAN Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.[1] [2] [3] [4] Publication Abstract from PubMedCasein kinase 2alpha (CK2alpha) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2alpha has a unique cryptic binding site, the alphaD 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 alphaD pocket. A drug discovery project to develop a new series of bivalent CK2alpha inhibitors with increased cell potency and selectivity identified 61f (APL-5125), a highly potent, ATP-competitive CK2alpha 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 CK2alpha inhibitors and is currently under evaluation in patients with advanced solid tumors. Exploiting the Cryptic alphaD Pocket of Casein Kinase 2alpha (CK2alpha) to Deliver Highly Potent and Selective Type 1 Inhibitors.,Glossop PA, Brear P, Wright S, Flanagan N, Glossop MS, Lane CAL, Butt RP, Spring DR, Hyvonen M, Cawkill D J Med Chem. 2025 Oct 14. doi: 10.1021/acs.jmedchem.5c01807. PMID:41085029[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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