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 our biochemical and cell-based assays, we have identified and isolated SIG1012, the PPM molecule in coffee. We have synthesized this small molecule and are currently performing structure function work on its derivatives. We believe this R&D effort will lead to novel pharma candidates for the prevention and treatment of CNS diseases and diabetes.

CNS Disease

Alzheimer’s Disease (AD)
In AD, neurodegenerative responses to inflammatory cytokines produced by plaques are exacerbated by PP2A deregulation. Recent research in the brain suggests that interference of PP2A methylation is a critical step in the onset of dementia in AD patients. A decrease in methylation interferes with PP2A trimer formation, reducing the dephosphorylation of tau -- a protein critical to the stability of neuronal microtubules. As tau protein becomes hyperphosporylated, it cross-links into the neurofibrillary tangles marking dementia and AD.

To offset this imbalance in PP2A activity and onset of AD, we have identified the active molecule in Cognion^™, SIG1012. This molecule likely interacts with PP2A, increasing PP2A net methylation levels, which enhances its phosphatase activity, blocking accumulation of hyperphosphorylated tau protein. 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. Similar to AD, SIG1012 and its derivatives have promising potential as small molecule therapeutics for PD.

Type 2 Diabetes
PP2A also plays a central role in the regulation of insulin secretion in pancreatic islet b-cells, and there is strong evidence that a component in coffee other than caffeine can act to prevent type-2 diabetes. Epidemiological data shows consumption of three or more cups a day of decaf correlates with a 52% decrease in diabetes. Thus, modulation of PP2A provides Signum with an attractive opportunity, to develop PPM compounds that treat diabetes.