Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL

Parsons, William H.; Rutland, Nicholas T.; Crainic, Jennifer A.; Cardozo, Joaquin M.; Andrews, Charlotte; Sheehan, Brendan K.

doi:10.1016/j.bmcl.2021.128290

Cited by 8 publications

(9 citation statements)

References 35 publications

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“…The pyrrolidine-2,5-dione ring is known to be a core fragment for many compounds with diverse therapeutic activities, i.e. , anticonvulsant, antipsychotic, antidepressant, anti-inflammatory, antibacterial, antiviral, or anticancer. , Our research has been focused for many years on the development of new succinimides acting on the CNS. The most recent studies led to the identification of several groups of pyrrolidine-2,5-dione derivatives, characterized by potent antiseizure and antinociceptive efficacy in preclinical studies. − Among these substances, N -benzyl-(2,5-dioxopyrrolidin-1-yl)propanamides represented by compounds I and II shown in Figure revealed especially favorable anticonvulsant and safety profiles. ,, Both compounds I and II showed antiseizure properties in commonly employed screening seizure models such as the maximal electroshock seizure test (MES), the subcutaneous pentylenetetrazol seizure test ( sc PTZ), as well as the 6 Hz seizure model (32 and 44 mA) in mice (Table ).…”

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

et al. 2022

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( R )-7 [ ( R )-AS-1 ] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. ( R )-7 [ ( R )-AS-1 ] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, ( R )-7 [ ( R )-AS-1 ] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

et al. 2022

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“…These strategies have since been widely employed to identify reversible SH inhibitors with novel reactivity. Recent examples include the discovery of hydroxymethyl(MIDA)boronate inhibitors for predicted carboxypeptidase CPVL, a SH whose endogenous substrates and function were poorly annotated [88] (Figure 7A, right); succinimide‐based sulfonyl ester and sulfonamide inhibitors for mitochondrial rhomboid protease PARL, a proteolytic regulator of mitophagy and cell death; [89] and a chymostatin inhibitor for protozoan carboxypeptidase and prolyloligopeptidase, two enzymes implicated in Leishmania mexicana parasitic diseases [90] . Cravatt and coworkers also further advanced their competitive ABPP strategy using kinetically‐tuned, moderately‐reactive triazole urea‐based probes to confirm in vivo target engagement of reversible amido piperazine LYPLA1 and LYPLA2 inhibitors [91] .…”

Section: Applications Of Serine Hydrolase Activity‐based Probesmentioning

confidence: 99%

Serine Hydrolase Activity‐Based Probes for Use in Chemical Proteomics

Racioppo

Qiu

Adibekian

2023

Israel Journal of Chemistry

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Serine hydrolases (SHs) comprise a large superfamily of enzymes that play critical roles in many biological processes. Despite their importance, many SHs remain uncharacterized and the vast majority of SHs lack selective inhibitors. In response, activity-based protein profiling (ABPP) and activity-based probes (ABPs) have been leveraged to construct a more comprehensive picture of the SH proteome. Since the utility of ABPP is largely dictated by the reactivity profile of the ABPs deployed, novel scaffolds and chemotypes are needed to expand the breadth and selectivity of SH-targeting ABPs. In this review, we highlight recent innovations in SH probe development, covering both established and emerging electrophilic warheads. We then discuss how strategic implementation of SH-targeting ABPs has yielded selective, potent inhibitors and imaging agents with broad use. Finally, we present methods for ABP diversification and explore cutting-edge applications in therapeutics development and discovery biology.

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“…Since PINK1-mediated mitophagy is dependent on its targeting to mitochondria whereas cleavage of PINK1 via proteases can dissociate PINK1 from mitochondria and therefore inhibit PINK1's function on mitophagy, suppressing proteases activity to cleave PINK1 is presumably able to enhance PINK1-dependent mitophagy process. In this regard, small-molecule inhibitors of the mitochondrial protease PARL that can cleave PINK1 could potentially enhance the activity of PINK1-depedendent mitophagy (Parsons et al, 2021).…”

Section: Mitochondrial Dependent Function Of Pink1mentioning

confidence: 99%

Mitochondrial-Dependent and Independent Functions of PINK1

Chen

Wang

et al. 2022

Front. Cell Dev. Biol.

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PINK1 has been characterized as a mitochondrial kinase that can target to damaged mitochondria to initiate mitophagy, a process to remove unhealthy mitochondria for protecting neuronal cells. Mutations of the human PINK1 gene are also found to cause early onset Parkinson’s disease, a neurodegenerative disorder with the pathological feature of mitochondrial dysfunction. Despite compelling evidence from in vitro studies to support the role of PINK1 in regulation of mitochondrial function, there is still lack of strong in vivo evidence to validate PINK1-mediated mitophagy in the brain. In addition, growing evidence indicates that PINK1 also executes function independent of mitochondria. In this review, we discuss the mitochondrial dependent and independent functions of PINK1, aiming at elucidating how PINK1 functions differentially under different circumstances.

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Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL

Cited by 8 publications

References 35 publications

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

Discovery of (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo

Serine Hydrolase Activity‐Based Probes for Use in Chemical Proteomics

Mitochondrial-Dependent and Independent Functions of PINK1

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