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LRRK2 PROTAC Degraders as a Potential Novel Targeting Strategy for Parkinson's Disease?

When the gene for the Park8 locus, LRRK2, was identified in 2004, its potentially druggable kinase domain and subsequently frequency, occurring in 1%–2% of all cases of Parkinson’s disease (PD), offered a compelling therapeutic rationale. Although pharmaceutical companies started to develop small-molecule kinase inhibitors, much of its biological role and potential non-catalytic function remain elusive. A milestone in 2016 was the discovery of a subset of Rab GTPases, including Rab10 as the first bona fide substrates of the LRRK2 kinase. LRRK2-dependent Rab phosphorylation mirrors LRRK2 kinase activity, serving as a biomarker in human bio-samples and as a functional readout. All pathogenic LRRK2 mutations enhance Rab phosphorylation, in a manner that is blocked by diverse small-molecule LRRK2 inhibitors. Indeed, LRRK2 kinase inhibitors are currently being evaluated in clinical trials. An alternative strategy is to target LRRK2 as a whole, for example, with antisense oligonucleotide, which is also being pursued in early-stage clinical trials (ClinicalTrials.gov Identifier: NCT03976349). However, Liu et al. just published a completely novel approach with the development of the first potent and selective LRRK2 proteolysis targeting chimera (PROTAC), XL01126. PROTACs utilize the cell’s own recycling machinery, the ubiquitinproteasome system (UPS). When proteins in a cell are destined for degradation, they are linked to an ubiquitin chain by an ubiquitin E3 ligase and thus marked for UPS degradation. PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase and another that binds to a target protein meant for degradation, here LRRK2. Through a multistep selection process in which 30 molecules were tested, the group successfully identified a very efficient LRRK2 degrader, XL01126. In mouse embryonic fibroblasts and human peripheral blood mononuclear cells, treatment with the LRRK2 degrader XL01126 resulted in a reduction in LRRK2 protein levels and subsequent Rab10 dephosphorylation with high potency and selectivity (DC50 values within 15–72 nM, Dmax values range from 82% to 90% and degradation half-lives span from 0.6 to 2.4 hours). Interestingly, it was shown that the inhibition appeared to be even stronger in cells carrying the PD causing G2019S mutation. Promising early results also show that XL01126 is orally bioavailable and can penetrate the blood brain barrier after either oral or parenteral dosing in mice. These discoveries provide hope that PROTACs may one day find their way into PD therapies. It also represents a great tool compound for further exploring the scaffolding non-catalytic biological roles of LRRK2.