Inhibition of CK2: An Attractive Therapeutic Target for Cancer Treatment.

Abstract

Summary: The invention in this patent application relates to pyrrolo[1,5-A]pyrimidine derivatives represented generally by formula (I). These compounds are inhibitors of CK2 and may potentially be used in the prevention and treatment of CK2-related conditions and diseases including cancer. The casein kinase 2 (CK2) is a serine/threonine-selective protein kinase that exists as a tetramer of two catalytic (α and/or α 0 ) subunitsand two regulatory(β) subunits.The level ofCK2 innormalcells is tightlyregulatedto performa variety ofessential roles suchascellcyclecontrol,cellulardifferentiationandproliferation,andpromotingcellsurvivalviamodulationofapoptoticpathways. Studies have shown that elevated levels of CK2 are associated with cancer, while targeted overexpression of CK2 in transgenic animalmodelsresultsinneoplasticgrowth.CK2phosphorylatesandregulatestheactivityandstabilityofmultipletumorsuppressor proteins such as PML, p53, and PTEN, as well as oncogenes and transcriptional activatorssuch as c-Myc, c-Myb, c-Jun, NFkB, and β-catenin. Recent studies provided evidence that CK2 can act as suppressor of apoptosis via phosphorylation of pro-apoptotic proteins, which protect them from caspase mediated cleavage. Studies also showed that inhibition of CK2 sensitizes cells to TNFrelated apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis, ionizing radiation and chemotherapeutic agents. Thus,inhibitionofCK2maybeaneffectivetherapeutictargetfortreatmentofcancer.Theinventorsstatedthatthecurrentlyavailable small molecule inhibitors of CK2 lack the necessary balance of potency, selectivity, and drug-like properties for consideration as therapeutic agents. The CK2 inhibitors described in this patent application may possess improved properties that would provide a potentially useful treatment for cancer.