The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. In the last 5 years, efforts to identify selective and brain-penetrant LRRK2 inhibitors have made significant advances. Prior to 2011, reported LRRK2 inhibitors were typically legacy compounds from previous kinase inhibitor programmes, with significant off-target kinase activities. These included the natural product staurosporine 1a and its derivative K-252a 1b [100], which inhibit wild-type LRRK2 (IC50 = 1-40 and 3.6-25 nM, respectively) as determined by radioactive, time-resolved fluorescence resonance energy transfer (TF-FRET) and AlphaScreen® in vitro assays, as well as the ROCK2 inhibitor H-1152 (2) [101] (wild-type LRRK2 IC50 = 244 nM and G2019S LRRK2 IC50 = 150 nM).

The kinase inhibitor field has focussed on developing therapeutics for oncology, although marketed kinase inhibitors are now available for idiopathic pulmonary fibrosis and arthritis [102]. Medicinal chemists have been adapting the properties of these molecules so that they are more aligned with the properties required for a CNS agent, with lower molecular weight, fewer hydrogen bonds and a cLogP optimally around 3 [103].

Nearly all compounds that have been reported are type I binders that compete with ATP. A study of the effect of type II kinase inhibitors with LRRK2 inhibitory activity concluded that it would be challenging to develop type II inhibitors for the G2019S mutation, due to stabilisation of the active kinase conformation by the Ser2019 [104].

The field has now matured so that tool compounds have become available for understanding LRRK2 biology in vitro and in vivo, and some of these have been progressed into advanced preclinical toxicology assessment. One of the principal challenges in their in vivo profiling is the absence of any preclinical models of PD that are modelled by LRRK2 dysfunction. Evidence of in vivo activity has been typically measured by indirect measurements of LRRK2 activity using LRRK2 Ser910 and Ser935 phosphorylation or directly using the LRRK2 Ser1292 autophosphorylation site.

In this review, these efforts towards the discovery of selective LRRK2 inhibitors will be discussed, grouped by chemotype. The reader is also directed to previous reviews of LRRK2 inhibitors [105—110].

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