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It is a rare event in drug discovery that mutations in a gene associated with the autosomal dominant forms of a disease, for which there is a large unmet medical need, affect a protein that belongs to a major class of drug targets. As a consequence, in recent years leucine‐rich repeat kinase 2 (LRRK2) has emerged as a major target candidate for therapies of Parkinson’s disease, and selective inhibitors of this kinase are being evaluated as possible new drugs for this detrimental disease. In this chapter, we review recent advances in the design of potent and selective LRRK2 inhibitors as well as the availability of models for their pharmacological evaluation. We also touch upon the challenges ahead – for further improvement of small molecule inhibitors and for in vivo pharmacological target validation.

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