Discovery of small molecule PINK1 activators as potential treatments for Parkinson’s Disease

Alghamdi, Arwa 2026. Discovery of small molecule PINK1 activators as potential treatments for Parkinson’s Disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

PINK1 has emerged as a promising drug target for Parkinson's disease (PD) treatment. Loss-of-function mutations in PINK1 cause early-onset familial PD, while its activation triggers mitophagy, a cellular process that selectively removes damaged mitochondria. By enhancing mitochondrial quality control, PINK1 activators reduce oxidative stress and protect against neurodegeneration. Small molecule PINK1 activators therefore represent a promising therapeutic strategy applicable to both sporadic and familial forms of PD. We designed and synthesized 25 small heterocyclic nucleobase mimics and screened a series of commercially available small molecules (n = 23) to identify novel PINK1 activators. Among these, compounds AM-A53 and AM-C29 activated PINK1 by 2.4–3.2-fold under basal conditions, while compounds AM-A21 and AM-C19 reduced CCCP-induced phosphoubiquitin accumulation by 30–40%. Notably, three commercially purchased compounds, AM-M02, AM-M03, and AM-M07, demonstrated robust PINK1 activation (12–56-fold increase of basal phosphoubiquitin) and reduced CCCPinduced phosphoubiquitin accumulation by 40–50%. Additionally, homobifunctional inducers of PINK1 dimerization were designed and synthesized aiming to promote PINK1 activation through enforced dimerization, though these did not activate PINK1. Parallel mechanistic investigations revealed that nucleoside activators reduce CCCP-induced phosphoubiquitin accumulation by inducing mitophagy and accelerating mitochondrial clearance rather than by inhibiting PINK1 kinase activity, as demonstrated by their activity in cellular assays but not in our kinase assays. Critical assay optimization established that DMSO concentrations must be ≤5% for accurate measurements and that redox conditions significantly affect PINK1 activity. Structural studies explored stabilization of human PINK1 in vitro by various metabolites and some of these induced dose-dependent inhibition. We also explored whether components of the mitochondrial membrane can affect PINK1 kinase activity. This was pursued through mutagenesis of PINK1, and mutations significantly impaired PINK1 activity. Collectively, our findings reveal that nucleoside and nucleobase-like compounds PINK1 activators reduce CCCPinduced phosphoubiquitin accumulation by accelerating mitophagy and identify three potent novel PINK1 activators as promising therapeutic leads, providing insights for designing next-generation therapeutics that enhance mitochondrial quality control in PD.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	16 April 2026
Last Modified:	16 Apr 2026 11:05
URI:	https://orca.cardiff.ac.uk/id/eprint/186428

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