Issue 9, 2022

Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle

Abstract

A series of oleic acid amide derivatives were synthesized based on our previous and continuing endeavors towards stimulation of the 20S core particle of the proteasome (20S CP) with the goal of increasing the protein degradation rate via the ubiquitin-independent pathway. The designed compounds were tested in a variety of biochemical and cell-based assays to assess their ability to increase the rate of hydrolysis of the 20S CP, and compared to a known fatty acid amide stimulator of the 20S CP, AM-404. AM-404 was previously described to stimulate the activity of the 20S CP, however, it does negatively affect viability of cells after prolonged dosing. Here we report the development of several small molecules with a similar ability to enhance the activity of the 20S CP as AM-404. While one molecule (17) was just as potent as AM-404, it still caused significant unwanted cytotoxicity. Molecules such as these are compatible with biochemical assays and short-term cell-based proteasome activity assays, but their unwanted toxicity limits their use in prolonged cell assays or in vivo studies.

Graphical abstract: Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle

Supplementary files

Article information

Article type
Research Article
Submitted
02 mai 2022
Accepted
15 juil. 2022
First published
26 juil. 2022

RSC Med. Chem., 2022,13, 1077-1081

Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle

S. Halder, N. J. Macatangay, B. L. Zerfas, A. F. Salazar-Chaparro and D. J. Trader, RSC Med. Chem., 2022, 13, 1077 DOI: 10.1039/D2MD00133K

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