Objective: Report on the pharmacological characteristics of small molecule PROteolysis TArgeting Chimera (PROTAC) molecules designed to induce degradation of leucine rich repeat kinase 2 (LRRK2) for the potential treatment of Parkinson’s disease (PD) and related neurodegenerative diseases.

Background: LRRK2 missense mutations are the most common cause of familial PD and LRRK2 variants are associated with increased risk for developing sporadic PD. LRRK2 mutations cause gain-of function increases in kinase activity and LRRK2 overactivation also has been observed in sporadic PD. Human genetics and pre-clinical studies have shown that reduction of LRRK2 kinase activity or expression is neuroprotective.

Method: LRRK2 PROTAC molecules were characterized pharmacologically in vitro and in vivo, across species, and in models of familial PD. LRRK2 degradation and pathway engagement were measured in different cellular systems and mechanism-of-action confirmed by ligand competition. In vivo characterization of PK/PD relationships were evaluated by relating LRRK2 PROTAC plasma and brain exposure to LRRK2 degradation and downstream phospho-RAB pathway engagement in the brain. PK/PD for LRRK2 kinase inhibitors were also evaluated for comparison. Drug exposure was measured by LC-MS/MS. LRRK2 protein levels were measured using a MSD immunoassay and phospho-RAB pathway engagement was assessed by immunoblot. Target selectivity was assessed by TMT proteomics.

Results: LRRK2 PROTAC molecules demonstrate robust and selective LRRK2 degradation and pathway engagement in cell-based models and in vivo.  Oral administration of LRRK2 PROTAC molecules demonstrate concentration-dependent reductions of LRRK2 protein in the brain. Assessment of LRRK2 degradation kinetics indicate that pharmacodynamic responses are durable and reversible. We demonstrate LRRK2 degradation in mouse, rat, and non-human primate after oral dosing, with robust biodistribution to deep anatomic brain regions. Lastly, we show LRRK2 PROTAC degraders more potently engage the target compared to kinase inhibitors.

Conclusion: LRRK2 PROTAC molecules demonstrate excellent in vitro and in vivo LRRK2 degradation and downstream pathway engagement, compare favorably to LRRK2 kinase inhibitors, and may represent a new class of disease modifying therapeutics for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-potent-orally-bioavailable-and-highly-selective-lrrk2-protac-degrader-molecules-as-potential-disease-modifying-therapeutics-for-parkinsons-disease/