9tm3
Monoclinic crystal structure of protein kinase CK2 catalytic subunit CK2alpha' (CSNK2A2 gene product) in complex with the indenoindole-precursor compound JC0151
Structural highlights
FunctionCSK22_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] Publication Abstract from PubMedProtein kinase CK2 is the subject of numerous studies in medicinal chemistry due to its involvement in the development of several diseases, primarily cancers. Its overexpression in tumor cells is related to key processes such as tumor immune evasion and cell proliferation. The scientific approach of this study aims to investigate the thermal shift assay (TSA) as a pre-screening tool and to complement it with a co-crystallization approach in post-screening. Therefore, the synthesis of seven small-molecule CK2 inhibitors derived from indeno[1,2-b]indoles was supplemented by 18 related derivatives from our in-house compound library. The 25 molecules belong to four sub-scaffolds, namely 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (D-0), 5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (D-1), 9-hydroxy-5H-indeno[1,2-b]indol-10-one (D-2), and 5H-indeno[1,2-b]indole-6,9,10-trione (D-3). The most active CK2 inhibitors identified by capillary electrophoresis (CE)-based assay belong to the D-1 sub-scaffold. In the TSA, these compounds also generate significant shifts of the melting temperature (Tm) of CK2, indicating a clear correlation between the results of the CE-based assay and those of the TSA. The contribution of co-crystallization in post-screening also demonstrated the effectiveness of D-1 sub-scaffold compared with D-0 sub-scaffold. Targeting Human Protein Kinase CK2 by a Library of Indeno[1,2-b]Indoles: Contribution of Thermal Shift Assay to Pre-Screening and Co-Crystallization to Post-Screening.,Guimaraes MM, Werner C, Leroy B, Charles J, Guillon J, Pinaud N, Mularoni A, Jean-Baptiste M, Ximenes P, Gast A, Prinz H, Aichele D, Goncalves AG, Marminon C, Bouaziz Z, Jose J, Delcros JG, Niefind K, Le Borgne M Arch Pharm (Weinheim). 2026 Aug;359(8):e70312. doi: 10.1002/ardp.70312. PMID:42544794[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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