Increased LRRK2 kinase activity has been identified as a risk factor for the development of Parkinson’s disease, and genetic ablation of LRRK2 is suggestive of morphological and/or functional changes in lung and kidneys of LRRK2 knock-out rodents. In an effort to assess the consequences of inhibiting LRRK2 kinase activity in preclinical species, structurally distinct and highly optimized small molecule diaminopyrimidine inhibitors were developed.  In addition to describing these lead optimization efforts, a fruitful collaboration between Genentech and The Michael J. Fox Foundation will also be presented. Highlights of this industry–non-profit collaboration include extensive profiling of LRRK2 inhibitors in repeat-dose preclinical safety studies, investigation of peripheral biomarkers, and supply of highly LRRK2 specific and brain-penetrant inhibitors for experimental investigation of LRRK2 biology and function.

Investigation of highly optimized LRRK2 kinase inhibitors in preclinical safety studies via a Michael J. Fox Foundation–Genentech collaboration

249th National Meeting (2015)

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