1. Academic Validation
  2. Synthesis and structure-activity relationships of USP48 deubiquitinylase inhibitors

Synthesis and structure-activity relationships of USP48 deubiquitinylase inhibitors

  • Arch Pharm (Weinheim). 2023 May 17;e2200661. doi: 10.1002/ardp.202200661.
Kevin Böhm 1 2 Eric Schulze-Niemand 1 Thilo Kähne 1 Elisa Siddiqui 1 Christian Täger 1 Daniel Ramsbeck 2 Mirko Buchholz 2 Michael Naumann 1
Affiliations

Affiliations

  • 1 Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany.
  • 2 Department of Drug Design and Target Validation MWT, Fraunhofer Institute for Cell Therapy and Immunology IZI, Biocenter, Halle, Germany.
Abstract

Ubiquitin-specific proteases represent a family of enzymes that catalyze the cleavage of ubiquitin from specific substrate proteins to regulate their activity. USP48 is a rarely studied USP, which has recently been linked to inflammatory signaling via regulation of the transcription factor nuclear factor kappa B. Nonetheless, a crystal structure of USP48 has not yet been resolved and potent inhibitors are not known. We screened a set of 14 commercially available USP inhibitors for their activity against USP48 and identified the USP2 inhibitor "ML364" as a candidate for further optimization. Using a ligand-based approach, we derived and synthesized a series of ML364 analogs. The IC50 concentrations of the new compounds to inhibit USP48 were determined in a deubiquitinylase activity assay by measuring the fluorescence intensity using tetra-ubiquitin rhodamine110 as substrate. A compound containing a carboxylic acid functionalization (17e) inhibited USP48 activity toward tetra-ubiquitin rhodamine110 with an IC50 of 12.6 µM. Further structure-based refinements are required to improve the inhibition activity and specificity.

Keywords

USP2; chemical synthesis; drug design; papain-like protease; ubiquitin-specific proteases.

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