Accelerated Discovery of Novel Ponatinib Analogs with Improved Properties for the Treatment of Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating and common neurodegenerative disease. New insights implicating c-Abl activation as a driving force in PD have opened a new drug development avenue for PD treatment beyond the symptomatic relief by L-DOPA. BCR-Abl inhibitors, which include nilotinib and ponatinib, have been found to inhibit this process, and nilotinib has shown improvement in outcomes in a 12-patient, nonrandomized trial. However, nilotinib is a potent inhibitor of hERG, a cardiac K⁺ channel whose inhibition increases risk of sudden death. We used our machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against hERG. Of our six novel compounds tested, we identified two that had c-Abl potencies comparable to nilotinib, but with significantly improved profiles regarding the hERG channel. Our best compound exhibited a hERG IC₅₀ of 12.1 μM (compared to nilotinib with an IC₅₀ of 0.45 μM and ponatinib with IC₅₀ of 0.767 μM). This work is a step forward for a machine learning enabled, multiparameter optimization of a chemical space and represents a significant advance in the development of novel Parkinson’s therapies.