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

Autor:	Halder S; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University 575 W Stadium Ave West Lafayette IN 47907 USA dtrader@purdue.edu., Macatangay NJ; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University 575 W Stadium Ave West Lafayette IN 47907 USA dtrader@purdue.edu., Zerfas BL; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University 575 W Stadium Ave West Lafayette IN 47907 USA dtrader@purdue.edu., Salazar-Chaparro AF; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University 575 W Stadium Ave West Lafayette IN 47907 USA dtrader@purdue.edu., Trader DJ; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University 575 W Stadium Ave West Lafayette IN 47907 USA dtrader@purdue.edu.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2022 Jul 26; Vol. 13 (9), pp. 1077-1081. Date of Electronic Publication: 2022 Jul 26 (Print Publication: 2022).
DOI:	10.1039/d2md00133k
Abstrakt:	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. Competing Interests: Prof. Trader is a shareholder and consultant for Booster Therapeutics, GmbH. Other authors declare no conflict of interest. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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