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

[Display omitted] •Activity-based protein profiling used to screen for inhibitors of protease PARL.•Discovery of two new chemical scaffolds for inhibiting rhomboid proteases.•Sulfonamides display selectivity for PARL over bacterial rhomboid GlpG.•Compounds able to engage intracellular target. While...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2021-10, Vol.49, p.128290-128290, Article 128290
Main Authors: Parsons, William H., Rutland, Nicholas T., Crainic, Jennifer A., Cardozo, Joaquin M., Chow, Alyssa S., Andrews, Charlotte L., Sheehan, Brendan K.
Format: Article
Language:English
Subjects:
Activity-based protein profiling
Benzenesulfonates - chemical synthesis
Benzenesulfonates - pharmacology
DNA-Binding Proteins - antagonists & inhibitors
Endopeptidases
Escherichia coli - enzymology
Escherichia coli Proteins - antagonists & inhibitors
HEK293 Cells
Humans
Membrane Proteins - antagonists & inhibitors
Metalloproteases - antagonists & inhibitors
Mitochondrial Proteins - antagonists & inhibitors
Protease inhibitor
Protease Inhibitors - chemical synthesis
Protease Inhibitors - pharmacology
Rhomboid protease
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - pharmacology
Succinimides - chemical synthesis
Succinimides - pharmacology
Sulfonamides - chemical synthesis
Sulfonamides - pharmacology
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Summary:[Display omitted] •Activity-based protein profiling used to screen for inhibitors of protease PARL.•Discovery of two new chemical scaffolds for inhibiting rhomboid proteases.•Sulfonamides display selectivity for PARL over bacterial rhomboid GlpG.•Compounds able to engage intracellular target. While the biochemistry of rhomboid proteases has been extensively studied since their discovery two decades ago, efforts to define the physiological roles of these enzymes are ongoing and would benefit from chemical probes that can be used to manipulate the functions of these proteins in their native settings. Here, we describe the use of activity-based protein profiling (ABPP) technology to conduct a targeted screen for small-molecule inhibitors of the mitochondrial rhomboid protease PARL, which plays a critical role in regulating mitophagy and cell death. We synthesized a series of succinimide-containing sulfonyl esters and sulfonamides and discovered that these compounds serve as inhibitors of PARL with the most potent sulfonamides having submicromolar affinity for the enzyme. A counterscreen against the bacterial rhomboid protease GlpG demonstrates that several of these compounds display selectivity for PARL over GlpG by as much as two orders of magnitude. Both the sulfonyl ester and sulfonamide scaffolds exhibit reversible binding and are able to engage PARL in mammalian cells. Collectively, our findings provide encouraging precedent for the development of PARL-selective inhibitors and establish N-[(arylsulfonyl)oxy]succinimides and N-arylsulfonylsuccinimides as new molecular scaffolds for inhibiting members of the rhomboid protease family.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2021.128290