Polypharmacological Targeting of G2019S Mutant LRRK2 and JNK3 for the Discovery of a Lead Compound against Parkinson's Disease.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder for which single-target therapeutic strategies have shown limited success. To address this challenge, we pursued a structure-based polypharmacological approach targeting both the hyperactive G2019S mutant of leucine-rich repeat kinase 2 (LRRK2G2019S) and c-Jun N-terminal kinase 3 (JNK3), two kinases implicated in PD pathogenesis. Virtual screening, de novo design, and biological evaluation identified N2-phenyl-9H-purine-2,6-diamine (NPPD)-based scaffolds as promising dual-target hits. Subsequent macrocyclization and systematic structure-activity relationship optimization led to inhibitors with improved potency and drug-like properties. Among these, compound 17 exhibited low-nanomolar enzymatic inhibition against both kinases and exceptional picomolar cellular potency against LRRK2G2019S. While optimal cellular activity against JNK3 remains challenging, compound 17 demonstrated a favorable kinome-wide selectivity profile. Pharmacokinetic studies revealed excellent oral exposure, moderate clearance, and efficient brain penetration without observable toxicity. Overall, this study identifies a promising lead compound with significant potential as a therapeutic agent for PD.