Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C

Lainé, Dramane I.; Palovich, Michael R.; McCleland, Brent W.; Petit-Jean, Emilie; Delhom, Isabelle; Xie, Haibo; Deng, Jianghe; Lin, Guoliang; Davis, Roderick; Jolit, Anaïs; Nevins, Neysa; Zhao, Baoguang; Villa, Jim; Schneck, Jessica L.; McDevitt, Patrick; Midgett, Robert; Kmett, Casey; Umbrecht, Sandra; Peck, Brian; Davis, Alicia B.; Bettoun, David

doi:10.1021/ml100212k

Cited by 45 publications

(47 citation statements)

References 37 publications

(64 reference statements)

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“…Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans. In 2010, GlaxoSmithKline pursued the work on cyanamide-based CatC inhibitors with a study of 3-substituted pyrrolidine nitriles (D. Laine, et al, 2011). The starting point of the study was a 3phenethyl derivative (compound 16), which displayed strong inhibitory potency against CatC, but no selectivity over other cathepsins.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Korkmaz¹,

Caughey²,

Chapple³

et al. 2018

Pharmacology & Therapeutics

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Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects mediated by these proteases in inflammatory/auto-immune disorders. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome (PLS). The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Korkmaz¹,

Caughey²,

Chapple³

et al. 2018

Pharmacology & Therapeutics

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“…More recently, industry-led efforts have generated some highly specific inhibitors, exemplified by compounds targeting USP7, an enzyme linked to the p53/MDM2 signalling axis (Kategaya et al, 2017;Lamberto et al, 2017;Turnbull et al, 2017;Gavory et al, 2018;Schauer et al, 2019). Some N-cyano pyrrolidines, which resemble known cathepsin C covalent inhibitors, have been reported in the patent literature to be dual inhibitors of UCHL1 and USP30 (Laine et al, 2011). High-throughput screening has also identified a racemic phenylalanine derivative as a USP30 inhibitor (Kluge et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation

et al. 2020

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The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. We present the characterisation of an N-cyano pyrrolidine compound, FT3967385, with high selectivity for USP30. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery, represents a robust biomarker for both USP30 loss and inhibition. A proteomics analysis, on a SHSY5Y neuroblastoma cell line model, directly compares the effects of genetic loss of USP30 with chemical inhibition. We have thereby identified a subset of ubiquitylation events consequent to mitochondrial depolarisation that are USP30 sensitive. Within responsive elements of the ubiquitylome, several components of the outer mitochondrial membrane transport (TOM) complex are prominent. Thus, our data support a model whereby USP30 can regulate the availability of ubiquitin at the specific site of mitochondrial PINK1 accumulation following membrane depolarisation. USP30 deubiquitylation of TOM complex components dampens the trigger for the Parkin-dependent amplification of mitochondrial ubiquitylation leading to mitophagy. Accordingly, PINK1 generation of phospho-Ser65 ubiquitin proceeds more rapidly in cells either lacking USP30 or subject to USP30 inhibition.

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“…More recently industryled efforts have generated some highly specific inhibitors, exemplified by compounds targeting USP7, an enzyme linked to the p53/MDM2 signaling axis (31)(32)(33)(34)(35). Some Ncyano pyrrolidines, which resemble known cathepsin C covalent inhibitors, have been reported in the patent literature to be dual inhibitors of UCHL1 and USP30 (36). Highthroughput screening has also identified a racemic phenylalanine derivative as a USP30 inhibitor (37).…”

Section: Introductionmentioning

confidence: 99%

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

Rusilowicz‐Jones

Jardine

Pinto-Fernández

et al. 2020

Preprint

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The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. It has been proposed as an actionable target to alleviate the loss of function of the mitophagy pathway governed by the Parkinson's Disease associated genes PINK1 and PRKN. We present the characterisation of a N-cyano pyrrolidine derived compound, FT3967385, with high selectivity for USP30. The compound is well tolerated with no loss of total mitochondrial mass. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery that directly interacts with USP30, represents a robust biomarker for both USP30 loss and inhibition. We have conducted proteomics analyses on a SHSY5Y neuroblastoma cell line model to directly compare the effects of genetic loss of USP30 with selective inhibition in an unbiased fashion. We have thereby identified a subset of ubiquitylation events consequent to mitochondrial depolarisation that are USP30 sensitive. Within responsive elements of the ubiquitylome, several components of the outer mitochondrial membrane transport (TOM) complex are most prominent. Thus, our data support a model whereby USP30 can regulate the availability of ubiquitin at the specific site of mitochondrial PINK1 accumulation following membrane depolarisation. In this model, USP30 deubiquitylation of TOM complex components dampens the trigger for the Parkin-dependent amplification of mitochondrial ubiquitylation leading to mitophagy. Accordingly, PINK1 generation of phospho-Ser65 Ubiquitin proceeds more rapidly and to a greater extent in cells either lacking USP30 or subject to USP30 inhibition.

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Discovery of Novel Cyanamide-Based Inhibitors of Cathepsin C

Cited by 45 publications

References 37 publications

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

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