Synthesis and biological evaluation of substituted indeno[1,2-b]indole derivatives as inhibitors of human protein kinase CK2

Nacereddine A, Marminon C, Bouaziz Z, Jose J, LeBorgne M

Abstract

Protein kinase CK2 is a ubiquitous serine/threonine kinase found in all eukaryotic cells. Known since 1954, CK2 is a newly validated therapeutic target, ideally suited for drugdesign, and has become for next decades a major target for inhibition. Up to date more than 400 substrates were identified as its substrate but its connection to any specificmetabolic event in the cell has not been known clearly. Human CK2 includes two catalytic subunits and two regulatory subunits . Catalytic subunit possesses a great numberof basic residues within the substrate recognition site. The subunits play a role in stabilizing the tetrameric conformation and recruiting substrate. Strong evidence indicates thatCK2 is a component of regulatory protein kinase networks that are involved in different human cancer types (e.g. prostate, breast, pancreas, hepatocellular carcinoma) and in viralinfections (e.g. hepatitis B virus X-associated protein 2, HBV-CP). Several ATP competitive inhibitors of CK2 have been discovered and only CX-4945 has been entered in phase Iclinical trial.