Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases

There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.

Kinases; Microtubule stabilization; Neurodegenerative diseases; α-Synuclein.