Many cellular signaling pathways are regulated through reversible phosphorylation by kinases and phosphatases, that introduce or remove phosphate groups respectively. With the recent advancement of protein kinase inhibitors (PKIs) into the clinic, increased drug discovery efforts are focusing on phospho-protein modulation as a therapeutic approach. PKIs have traditionally been developed as therapeutic candidates, but recent drug discovery efforts are focusing on modulating phosphatases, as an alternative therapeutic approach (Gong et al. ’06, Honkanen + Golden ’02). Signum Biosciences’ PPM technology targets specific phosphatases, and causes the same net result as PKIs: decreased protein phosphorylation. Similar to PKIs, PPMs that increase phosphatase activity yield the same net result, decreased protein phosphorylation levels However, the uniqueness of our approach to an AD therapeutic is in targeting PP2A. While tau is phosphorylated by at least five distinct protein kinases (Iqbal et al. ‘09), PP2A is the major tau phosphatase accounting for ~70% of tau dephosphorylation (Lui et al. ‘05). Dysregulation of the tau phosphorylation cycle has been recognized as an attractive therapeutic target (Gong et al. ’06, Mi + Johnson ’06, Deutsch et al. ‘06). We anticipate that our PPM technology will be effective in developing novel, disease-modifying AD therapeutics.
Methylation Regulates PP2A
The PP2A ‘holoenzyme’ is composed of a highly active AC core dimer (scaffold A subunit and catalytic C subunit) that binds to several different regulatory B subunits. Methylation at a highly conserved carboxy-terminal leucine residue of the C subunit, is catalyzed by a specific PP2A-methyltransferase (PPMT), while a PP2A-specific methylesterase (PPME) removes the methyl group. Together these protein antagonists comprise the PP2A methylation system that controls the assembly of fully functional PP2A heterotrimers. Low levels of AC dimer methylation in Alzheimer’s disease correlate well with deficiencies in PP2A activity, leading to hyperphosphorylated tau, and the formation of neurofibrillary tangles (Sontag et al. ’04). Signum’s PPM compounds target PP2A and its methylation system, playing a key modulatory role in the heterotrimers ability to assemble and disassemble. PPMs enhance PP2A activity towards tau so as to reduce tau phosphorylation and disease progression.
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