Leucine-rich repeat kinase 2 (LRRK2) gain of function mutations are associated with late-onset autosomal dominant Parkinson's disease (PD) and represent the most common known cause of familial PD. In spite of strong genetic evidence for potential disease modification in PD patients, advancement of LRRK2 inhibitors towards the clinic has been hampered by many factors, including perceived on-target toxicology in preclinical species. To further investigate these findings, medicinal chemistry efforts provided a potent, selective, brain-penetrant tool molecule enabling further investigation of the mechanism internally and with collaborators via the Michael J. Fox Foundation (MJFF). This tool has not only been utilized to understand the effects of LRRK2 inhibitors pathologically and functionally, but also to further interrogate efficacy of LRRK2 inhibition in preclinical models and to elucidate substrates of LRRK2 that aid in biological understanding and could be useful as clinical biomarkers. This compilation of data and our efforts toward identifcation of a high quality molecule for clinical development will be discussed.

Leveraging pre-competitive risk sharing to accelerate understanding of LRRK2 kinase inhibition

251st National Meeting (2016)

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