STM Platform » PPM Pharmaceutical Development

Signum has an intensive research program to identify PPMs by screening for compounds that affect the regulation of PP2A, the major phosphoprotein phosphatase in the CNS. Using proprietary biochemical and cell-based assays, we identified our lead candidate SIG1012. We are currently performing structure-function work to generate 2nd generation PPM molecules. We believe this R&D effort will lead to novel pharma candidates for the prevention and treatment of CNS disease.

Introduction: Alzheimer's Disease

The two key hallmarks of Alzheimer’s Disease (AD) brain pathology, amyloid plaques and neurofibrillary tangles (NFTs), were described over a century ago by Dr. Alois Alzheimer. Plaques are formed by the generation and accumulation of amyloid beta peptide (Abeta), while NFTs are caused by abnormal hyperphosphorylation and aggregation of tau, a microtubule-associated protein. Although the etiology of AD is not completely understood, the most widely accepted view is that the accumulation of Abeta is a key initiating event that eventually leads to the accumulation of NFTs, followed by neuronal degeneration and dementia (termed Amyloid cascade hypothesis). As such, a large part of drug development efforts for AD currently target either the formation or removal of beta-amyloid (Seabrook et al. ‘07). However, several lines of evidence indicate the Amyloid cascade hypothesis is too simplistic (Small + Duff ‘08) and that abnormal tau hyperphosphorylation and subsequent NFT formation are not just critical steps in neurodegeneration, but are themselves likely to be key initiating events.

• NFTs can cause neurodegeneration in the absence of  plaques (Hutton et al. ’98, Poorkaj et al. ’98)
• Hyperphosphorylated tau is a common feature in a number of neurodegenerative diseases named tauopathies
• Some normal aged individuals show plaque levels similar to those with AD (Iqbal et al. '08)
• NFTs but not plaques parallel duration and severity of AD (Arriagada et al. ’92)
• Amnestic mild cognitive impairment, a precursor to AD, is associated with NFT accumulation and not plaques (Markesbery et al. ’06)
• In an AD mouse model, animals possessing large amounts of plaques, but lacking tau, had no decline in cognition. Animals possessing tau were impaired (Roberson et al. ’07)
• Disappointing results of Abeta-reducing drugs in human clinical trials (e.g. Flurizan (Myriad Genetics), bapineuzumab (Wyeth/Elan) and tramiprosate (Neurochem))

The inhibition of abnormal hyperphosphorylation of tau is one of the most promising therapeutic approaches for the development of diseasemodifying drugs in AD (Iqbal et al. '08). Signum Biosciences’ novel approach targets the major phosphatase for tau in the brain, protein phosphatase 2A (PP2A). By developing Phospho-Protein Modulators (PPMs) we seek to restore abnormal tau phosphorylation to normal levels, providing a new treatment for AD.

Neurons play a key role in processing and transmitting information in brain cells. In healthy neurons, tau binds to microtubules (MTs) promoting MT assembly and stability. Regulation of these two tau functions occurs primarily through the interplay of several tau kinases and PP2A dephosphorylation. When tau phosphorylation levels remain “normal”, structural integrity of MTs is maintained, resulting in functional, viable neurons. However, in diseased neurons tau becomes abnormally hyperphosphorylated no longer stimulating MT assembly, resulting in polymerization of tau into paired helical filaments (PHFs) and NFTs (see figure below). Moreover, the hyperphosphorylated tau remaining in the cytosol (not aggregated) sequesters normal tau and other major MT associated proteins promoting further MT disassembly and ultimately neuronal death.

One such cause for this deregulation of tau phosphorylation is a decrease in PP2A activity. Recent research in the brain suggests that reduction in PP2A methylation is a critical step in the onset of dementia in AD patients ( Sontag et al. ’07).        A decrease in methylation interferes with PP2A trimer formation, reducing the dephosphorylation of tau (Sontag et al. ’08, Zhou et al. ’08, Yoon et al. ’07, Sontag et al. ’04, Vafai + Stock ’02). Also, it has been previously shown that the activity of PP2A is compromised by ~20% in AD brains (Gong et al. ’95, Gong et al. ‘93). Signum’s PPM molecules interact with the PP2A methylation system to increase net methylation levels, thereby enhancing phosphatase activity and reducing the hyperphosphorylation of tau. SIG1012 and its derivatives have promising potential as small molecule therapeutics for AD.

Parkinson’s Disease (PD)
Similar to AD, there is strong evidence for PP2A deregulation in PD. Several studies have shown that α-synuclein proteins become hyperphosphorylated leading to Lewy bodies in PD. By virtue of their ability to enhance PP2A methylation, PPMs have promising potential as small molecule therapeutics for PD.