An orally bioavailable and blood-brain hurdle penetrating analog of the kinase inhibitor K252a was able to prevent the standard engine deficits in the tau (P301L) transgenic mouse magic size (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases including tau pathology. (6). These observations suggest that irregular hyperphosphorylation of tau may play a role in the pathogenesis of tauopathies by inducing microtubule network breakdown followed by neuritic atrophy and neurodegeneration. Additionally hyperphosphorylated and/or aggregated varieties Brivanib of tau may exert direct toxic effects on neurons (7). It is important to recognize however that most phosphorylation-related antigenic markers of tau also are found in the normal mind if postmortem dephosphorylation artifacts are minimized and can become reconstituted by a broad range of proline-directed kinases (8). Indeed basal phosphorylation levels at some of these sites within tau are thought to play an important role in the normal rules of tau function and microtubule dynamics (9). Although it is definitely obvious that aberrant phosphorylation of the tau protein is definitely a defining and invariable feature from the neurofibrillary tangles (NFTs) and neuropil threads (NTs) in Advertisement the large number of phosphorylation sites within tau as well as the complexity from the causing phosphorylation patterns provides hindered the unambiguous id from the relevant proteins kinases adding to both regular and unusual phosphorylation under pathological circumstances. Various kinases have already been implicated particularly in unusual hyperphosphorylation from the 17 Ser/Thr-Pro motifs generally in charge of the diagnostic antigenic properties of pathological tau types (analyzed Rabbit polyclonal to LAMB2. in refs. 8 and 10). extracellular signal-regulated kinase (ERK) 2 is a especially conspicuous candidate due to its capability to phosphorylate each one of these sites up to the maximal stoichiometry (11 12 an capability matched just by SAPK4 also to a somewhat lesser Brivanib level by SAPK3 (ERK6) (13). As a result actually disease-specific tau phosphoepitopes such as those related to particular Ser-422 phosphorylation-dependent epitopes (14) are fully reconstituted by ERK2 but not by additional known tau-kinases like cdk5 or GSK3 which phosphorylate tau only to lower stoichiometric ratios. The finding that activated forms of ERK1 and ERK2 colocalize with the neurofibrillary lesions in postmortem AD brains (15 16 also is compatible with a role for ERKs in the pathological hyperphosphorylation of tau. Here we report a significant reduction in the levels of irregular hyperphosphorylated tau varieties and prevention of the severe engine impairments in JNPL3 Brivanib transgenic mice expressing P301L mutant human being tau after chronic treatment having a previously undescribed small molecule inhibitor of ERK2 albeit one of limited selectivity. Our Brivanib findings provide clear evidence that inhibition of pathological tau hyperphosphorylation can delay or prevent tau-related practical deficits and support the use of such inhibitors as an approach to developing a disease modifying treatment for tau-related neurodegenerative disease. Results Despite extensive testing efforts for small molecule inhibitors of ERK2 only the known natural product K252a produced useful inhibitory activity for ERK2 a hitherto unappreciated house of this normally well known compound (Fig. 1(G.H. S. Geis S.L.C. S. Gordon R. Francasso S. Ferrand H.W.K. and H.M.R. unpublished data). A medicinal chemistry program consequently was initiated to optimize the K252a lead structure for any proof of concept experiment in tau transgenic mouse models (17 18 Fig. 1. Chemical structure and pharmacokinetics of SRN-003-556. (and in the presence of 250 μM of ATP with Brivanib IC50 ideals of 0.6 0.18 0.35 0.44 and 0.26 μM respectively. Pathological hyperphosphorylation of tau at multiple proline directed serine and threonine sites as induced by okadaic acid was potently prevented by SRN-003-556 in adult rat hippocampal slices (Fig. 2). Amazingly SRN-003-556 treatment (Fig. 2) resulted in inhibition of tau phosphorylation in the promiscuous AT8 phosphoepitope (site related to.