Neo-212

Temozolomide Perillyl Alcohol Conjugate NEO212 is an orally bioavailable agent composed of the prodrug and alkylating agent temozolomide (TMZ), a triazene analog of dacarbazine, covalently conjugated to perillyl alcohol (POH), a naturally occurring monoterpene, with potential antineoplastic activity. Upon oral administration of temozolomide perillyl alcohol conjugate NEO212, TMZ is converted at physiologic pH to the short-lived active compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC is rapidly degraded into a methyldiazonium ion that methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication and the induction of apoptosis. In addition, NEO212 may decrease the focal adhesion kinase (FAK)/Src signaling pathway and the production of certain matrix metalloproteinases (MMPs), and may block and reverse the epithelial-to-mesenchymal transition (EMT) process. This may reduce tumor cell migration and invasion. Also, NEO212 promotes mitochondrial dysfunction and induces mitochondrial apoptosis, inhibits the nuclear translocation of transcription factor EB (TFEB), and impairs the lysosomal function and blocks the autophagy flux in susceptible tumor cells. Like TMZ, NEO212 crosses the blood-brain-barrier (BBB). Compared to TMZ alone, NEO212 stabilizes the prodrug TMZ, and allows better BBB penetration, greater cellular uptake and increased potency.