Optimization of pyrazolopyrimidines lead to the identification of a highly selective casein kinase 2 inhibitor

Abstract

ABSTRACTCasein kinase 2 (CK2) is a constitutively expressed serine/threonine kinase that has a large diversity of cellular substrates. Thus, CK2 has been associated with a plethora of regulatory functions and dysregulation of CK2 has been linked to disease development in particular to cancer. The broad implications in disease pathology makes CK2 an attractive target. To date, the most advanced CK2 inhibitor is silmitasertib, which has been investigated in clinical trials for treatment of various cancers, albeit several off-targets for silmitasertib have been described. To ascertain the role of CK2 inhibition in cancer, other disease and normal physiology the development of a selective CK2 inhibitor would be highly desirable. In this study we explored the pyrazolo[1,5-a]pyrimidine hinge-binding moiety for the development of selective CK2 inhibitors. Optimization of this scaffold, which included macrocyclization, led to IC20 (31) a compound that displayed high in vitro potency for CK2 (KD = 12 nM) and exclusive selectivity for CK2. X-ray analysis revealed a canonical type-I binding mode for IC20. However, the polar carboxylic acid moiety that is shared by many CK2 inhibitors including silmitasertib was required for potency and reduced somewhat cellular activity. In summary, IC20 represents a highly selective and potent inhibitor of CK2, which can be used as a tool compound to study CK2 biology and potential new applications for the treatment of diseases.Notes The authors declare no conflict of interest.Competing Interest StatementThe authors have declared no competing interest.Abbreviations2-MTHF2-methyltetrahydrofuranATPAdenosine triphosphateB2pin2Bis(pinacolato)diboronCK2Casein kinase 2DIADdiisopropyl azodicarboxylateDIPEAN,N-diisopropylethylamineHEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidIPTGIsopropyl-thio-galactopyranosideMES2-(N-morpholino)ethanesulfonic acidMGCmammalian gene collectionPEG MMEpolyethylene glycol monomethyl etherP(Cy)3TricyclohexylphosphineTCEPTris(2-carboxyethyl)phosphineTEVTobacco Etch VirusTf2Otrifluoromethanesulfonic anhydrideTPP triphenylphosphine;XPhos2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylView Full Text