Phenserine, a derivative of physostigmine, was first described as an inhibitor of acetylcholinesterase (AChE) and was shown to improve cognition in various experimental paradigms in rodents and dogs. It was clinically tested for Alzheimer's disease, with moderate success in initial Phase II studies. Phenserine is also unique because of differing actions of its enantiomers: (-)-phenserine is the active enantiomer for inhibition of AChE, whereas ( )-phenserine (Posiphen®) has weak activity as an AChE inhibitor and can be dosed much higher. Posiphen® is a small, hydrophobic, orally available molecule that enters the brain readily. It is the only drug ever described that inhibits more than one neurotoxic aggregating protein. Posiphen® inhibits synthesis of amyloid precursor protein (APP), tau and α-Synuclein. mRNA translation of neurotoxic aggregating proteins is up-regulated by iron (Fe) and down-regulated by iron regulatory protein-1 (IRP1). Posiphen® interferes with this second step of the common cascade of the aggregating proteins. It enhances the binding and/or activity of IRP1 to the iron response element (IRE) stem loop in the 5’UTR of the mRNAs of neurotoxic aggregating proteins, therefore specifically lowering their synthesis. By potentiating the IRE/IRP1 complex, Posiphen® lowers the level of free mRNA to be translated by the ribosome. Posiphen® is in development for the treatment neurodegenerative diseases.

Senexin B is a selective CDK8/CDK19 inhibitor developed by Senex Biotechnology Inc. Senexin B is an ATP pocket binder, with very high target selectivity as indicated by kinome profiling. CDK8/19 inhibition produces chemopotentiating, chemopreventive and anti-metastatic effects in different types of cancer.