LRRK2 is a therapeutic target for Parkinson’s Disease (PD) and other neurodegenerative disorders. LRRK2 missense mutations are the most common cause of familial PD, and LRRK2 variants are associated with an increased risk of developing sporadic PD. LRRK2 mutations cause gain-of-function increases in kinase activity and LRRK2 overactivation also has been observed in sporadic PD. LRRK2 is a multidomain GTPase/ kinase that acts, in part, as a scaffolding protein to interact with components of downstream signaling pathways regulating: lysosomal function, mitochondrial processes, neuroinflammation, and alpha-synuclein accumulation to negatively impact neuronal survival. Human genetics and preclinical animal model data suggest that reduction of 50% of LRRK2 protein may impact pathology and dysfunction in PD. Therefore, reduction of LRRK2 in the brain may be beneficial for the treatment of PD. We have identified potent, selective, orally bioavailable LRRK2 PROTAC® protein degraders that cross the blood brain barrier in preclinical species and biodistribute to deep brain regions impacted in PD.

Optimizing LRRK2-Targeting PROTAC® Protein Degraders For Selectivity and to Cross the Blood-Brain Barrier Following Oral Administration

Arvinas has optimized selected LRRK2 PROTAC® protein degraders to show improved potency and degradation in the brain following a single oral administration in mice. In the left panel below, PROTAC-B (purple circles) has been optimized for improved LRRK2 potency in the cortex of the mouse brain compared to PROTAC-A (orange circles) following a single oral administration of different dose levels. In the panel on the right, following a single oral PROTAC® administration, the concentration of PROTAC® in the brain (in open circles- right Y-axis) induces durable 50% degradation of the LRRK2 protein (orange squares- left Y-axis) for two to three days. As the PROTAC® is cleared from the brain over time (to the lower limit of quantification (lloq)), LRRK2 protein in orange squares is resynthesized and restored to the baseline protein expression level. These data show that PROTAC® degrader molecules are eliminated from the brain and the LRRK2 protein is resynthesized within days, which is unlike genomic modalities where the target protein may be impacted for months or longer.

Chart Description:A single oral administration of our PROTAC® protein degrader rapidly degrades LRRK2 in brain (concentration-dependent and durable)

CTL:Vehicle Control; DC50:half-maximal degradation concentration; M: Molar

As shown below, our BBB-penetrant LRRK2 PROTAC® molecules have been shown to demonstrate very high selectivity for degradation of the LRRK2 protein (orange circle), compared to many other proteins measurable by mass spectroscopy (in purple circles) in the mouse brain cortex 24 hours following a single oral (PO) administration, and this selectivity was highly statistically significant (p > 10^-17).

Chart Description: Arvinas’ oral LRRK2 PROTAC® protein degrader molecule is highly selective in the brain

Our BBB-penetrant oral PROTAC® molecules can be optimized to show degradation of the LRRK2 protein in the brain across species (see Keystone Presentation) and broadly biodistributed to deep anatomic regions of the primate brain. As shown in the figure below, following oral administration the LRRK2 PROTAC® -induced degradation of LRRK2 across the primate brain including the cortex, striatum, caudate (not shown), and cerebellum. These brain regions are important in neurodegenerative diseases and are difficult for biologic and genomic modalities to get to by intravenous or intrathecal dosing routes (respectively).Thus, further differentiating our BBB-penetrant PROTAC® technology as a modality that can be orally administered and can uniformly biodistribute across the brain.

Chart Description: Oral PROTAC®-induced LRRK2 degradation with biodistribution to deep brain regions

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. PROTAC® protein degradation has the potential to enable selective targeting of mutant HTT (mHTT) protein. We have identified novel ligands that, when incorporated into a PROTAC® protein degrader molecule, induce potent and selective degradation of mHTT (shown in the panel below, in purple). Protein degradation requires binding to both the target (competed by addition of mHTT ligand in pink circles) and E3 ligase (E3-dead PROTAC in orange circles). The PROTAC® molecule induces potent degradation of mHTT (in purple) while sparing the protein produced by the wild-type HTT allele (WT HTT shown in blue).

Chart Description: Huntington’s Disease: Ligand chemistry enables allele-selective PROTAC® degradation of mHTT

Alpha-synuclein (α-syn) is an abundant neuronal protein that localizes predominantly to presynaptic terminals within the brain. While the precise normal function of this protein is not fully understood, the pathologic aggregation of α-syn is implicated in synucleinopathies. The most common of these diseases is Parkinson’s.

Arvinas is working on approaches to degrade α-syn and remove this protein from neurons that lead to pathology in diseases such as Parkinson’s Disease, multiple system atrophy, and Lewy body dementia.