GZD824 is a novel orally bioavailable Bcr-Abl inhibitor for Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 of 0.34 nM and 0.68 nM, respectively. In vivo efficacy studies in mouse xenograft or allograft models of human leukemia demonstrated that GZD824 successfully suppressed the growth of tumors driven by native Bcr-Abl, Bcr-Abl T315I, Bcr-Abl G250E, Bcr-Abl Q252H, Bcr-Abl E255K and Bcr-Abl F317L. GZD824 also provided a significant survival benefit leukemia model mice allografted with luciferase-expressing Ba/F3 cells driven by the mutant Bcr-Abl T315I kinase. The potential for compound GZD824 to overcome all of the Bcr-Abl mutations that result in clinically acquired resistance to imatinib indicates that this novel Bcr-Abl inhibitor is a promising lead candidate for further development. GZD824 has also being shown to suppresses pre-B ALL cells through inhibition of the SRC kinase and PI3K/AKT pathways and may be a potential therapeutic agent for the management of pre-B ALL.

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.