Tamoxifen Inhibits CDK5 Kinase Activity by Interacting with p35/p25 and Modulates the Pattern of Tau Phosphorylation

Cyclin-dependent kinase 5 (CDK5) is a multifunc-tional enzyme that plays numerous roles, notably inbrain development. CDK5 is activated through itsassociation with the activators, p35 and p39, ratherthan by cyclins. Proteolytic procession of the N-ter-minal part of its activators has been linked to Alz-heimer’s disease and various other neuropathies.The interaction with the proteolytic product p25 pro-longs CDK5 activation and modifies the substratespecificity.Inordertodiscoversmall-moleculeinhib-itors of the interaction between CDK5 and p25,we have used a bioluminescence resonance energytransfer (BRET)-based screening assay. Among the1,760compoundsscreened,thegenericdrugtamox-ifen has been identified. The inhibition of the CDK5activity by tamoxifen was notably validated by moni-toring the phosphorylation state of tau protein. Thestudy of the molecular mechanism of inhibition indi-cates that tamoxifen interacts with p25 to block theCDK5/p25 interaction and pave the way for newtreatments of tauopathies.