LAUSR

ABSTRACT Introduction: Disease-modifying treatment for Parkinson’s disease (PD) to halt or revert the disease progression remains an unmet medical need. LRRK2 kinase activity is abnormally elevated in PD patients carrying LRRK2 mutations, with G2019S as the most frequent one. Small molecules to inhibit LRRK2 kinase activity might provide a potential disease-modifying strategy for PD. Areas covered: This review provides an update of small molecule LRRK2 inhibitors in patents published from January 2014 to October 2019. The molecules are classified by their structural scaffolds. Expert opinion: Despite the tremendous efforts to push small molecule LRRK2 inhibitors toward clinical trials, the overall progress is somewhat disappointing due to the challenges in compound optimization and the putative concern of target-related adverse effects. It is challenging to optimize multiple parameters including kinase selectivity, CNS penetration, and unbound fraction in brain simultaneously. In addition, the on-target effect of morphologic changes observed in lung/kidney in pre-clinical studies for several frontrunner ATP-competitive inhibitors prevented their further development. With this regard, non-ATP-competitive inhibitors may provide a different safety profile for development. DNL201 and DNL151 have entered early clinical trials to evaluate tolerability and target engagement biomarkers. This will pave the way for the development for future LRRK2 inhibitors.