Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase

Shlevkov, Evgeny; Murugan, Param; Montagna, Dan; Stefan, Eric; Zorba, Adelajda; Harvey, James S.; Kumar, P. Rajesh; Entova, Sonya; Bansal, Nupur; Bickford, Shari; Wong, Li Chin; Hirst, Warren D.; Weihofen, Andreas; Silvian, Laura

doi:10.1016/j.isci.2021.103650

Cited by 14 publications

(16 citation statements)

References 51 publications

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“…An alternative target could be the E3-Ubiquitin ligase Parkin, which is also genetically linked to PD. However, Parkin is a less attractive therapeutic target because it is present constitutively, can affect proteasome-mediated degradation, and is difficult to activate pharmacologically (Shlevkov et al, 2022). Our group and others previously published that the neo-substrate kinetin tri-phosphate (KTP) could be used as an alternative phospho-donor by PINK1 with higher catalytic efficiency than ATP, and that the pro-drug kinetin could be taken up by cells and converted to KTP (Hertz et al, 2013; Osgerby et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

Chin

Rakhit

Ditsworth

et al. 2023

Preprint

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PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological alpha-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD.

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Section: Discussionmentioning

confidence: 99%

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

Chin

Rakhit

Ditsworth

et al. 2023

Preprint

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“…The development of small molecule Parkin enzyme activators has remained extremely challenging in the field to date. Biogen has recently identified a number of compounds that act as positive allosteric modulators of Parkin ( Shlevkov et al, 2022 ). These compounds sensitize Parkin to the activating effect of pUb or the W403A mutation but fail to enhance Parkin recruitment or mitophagy.…”

Section: Discussionmentioning

confidence: 99%

Structure-based design and characterization of Parkin-activating mutations

et al. 2023

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Autosomal recessive mutations in the Parkin gene cause Parkinson’s disease. Parkin encodes an ubiquitin E3 ligase that functions together with the kinase PINK1 in a mitochondrial quality control pathway. Parkin exists in an inactive conformation mediated by autoinhibitory domain interfaces. Thus, Parkin has become a target for the development of therapeutics that activate its ligase activity. Yet, the extent to which different regions of Parkin can be targeted for activation remained unknown. Here, we have used a rational structure-based approach to design new activating mutations in both human and rat Parkin across interdomain interfaces. Out of 31 mutations tested, we identified 11 activating mutations that all cluster near the RING0:RING2 or REP:RING1 interfaces. The activity of these mutants correlates with reduced thermal stability. Furthermore, three mutations V393D, A401D, and W403A rescue a Parkin S65A mutant, defective in mitophagy, in cell-based studies. Overall our data extend previous analysis of Parkin activation mutants and suggests that small molecules that would mimic RING0:RING2 or REP:RING1 destabilisation offer therapeutic potential for Parkinson’s disease patients harbouring select Parkin mutations.

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“…Small molecules that can induce similar conformation changes as these compensatory mutations may be used to restore activity of hypomorphic Parkin in specific EOPD patients. Furthermore, these small molecules provide an attractive alternative to direct activators of the auto-inhibited form of Parkin that may have limited potential and a small therapeutic window [ 84 ]. Alternatively, molecules that selectively enhance Parkin activity in the brain may be explored e.g.…”

Section: Parkin and Pink1 Activatorsmentioning

confidence: 99%

Therapeutic targeting of mitophagy in Parkinson's disease

Masaldan

Callegari

Dewson

2022

Biochemical Society Transactions

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Parkinson's disease is a neurodegenerative disorder characterised by cardinal motor symptoms and a diverse range of non-motor disorders in patients. Parkinson's disease is the fastest growing neurodegenerative condition and was described for the first time over 200 years ago, yet there are still no reliable diagnostic markers and there are only treatments that temporarily alleviate symptoms in patients. Early-onset Parkinson's disease is often linked to defects in specific genes, including PINK1 and Parkin, that encode proteins involved in mitophagy, the process of selective autophagic elimination of damaged mitochondria. Impaired mitophagy has been associated with sporadic Parkinson's and agents that damage mitochondria are known to induce Parkinson's-like motor symptoms in humans and animal models. Thus, modulating mitophagy pathways may be an avenue to treat a subset of early-onset Parkinson's disease that may additionally provide therapeutic opportunities in sporadic disease. The PINK1/Parkin mitophagy pathway, as well as alternative mitophagy pathways controlled by BNIP3L/Nix and FUNDC1, are emerging targets to enhance mitophagy to treat Parkinson's disease. In this review, we report the current state of the art of mitophagy-targeted therapeutics and discuss the approaches being used to overcome existing limitations to develop innovative new therapies for Parkinson's disease. Key approaches include the use of engineered mouse models that harbour pathogenic mutations, which will aid in the preclinical development of agents that can modulate mitophagy. Furthermore, the recent development of chimeric molecules (AUTACs) that can bypass mitophagy pathways to eliminate damaged mitochondria thorough selective autophagy offer new opportunities.

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Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase

Cited by 14 publications

References 51 publications

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

Structure-based design and characterization of Parkin-activating mutations

Therapeutic targeting of mitophagy in Parkinson's disease

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