ArticleBioorganic & medicinal chemistry letters2019
Analysis of chain length, substitution patterns, and unsaturation of AM-404 derivatives as 20S proteasome stimulators.
Article in Bioorganic & medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Recent Advancements in 20S Proteasome Enhancement: Degradation of Undruggable Targets.ACS medicinal chemistry letters · 2025Review
- Oleanolic Acid Amide Derivatives as 20s Proteasome Stimulators.Chembiochem : a European journal of chemical biology · 2025Article
- Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome.ACS chemical biology · 2025Article
- Proteasome Activators and Ageing: Restoring Proteostasis Using Small Molecules.Sub-cellular biochemistry · 2024Review
- Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators.ACS omega · 2023Article
- Oleic amide derivatives as small molecule stimulators of the human proteasome's core particle.RSC medicinal chemistry · 2022Article
- Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.Biomedicines · 2022Article
- Advances in Proteasome Enhancement by Small Molecules.Biomolecules · 2021Review
- Protein degradation profile reveals dynamic nature of 20S proteasome small molecule stimulation.RSC chemical biology · 2021Article
- Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.Bioorganic & medicinal chemistry letters · 2021Article
- Fluorescent Probes with Unnatural Amino Acids to Monitor Proteasome Activity in Real-Time.ACS chemical biology · 2020Article
- New Peptide-Based Pharmacophore Activates 20S Proteasome.Molecules (Basel, Switzerland) · 2020Article
- Proteasome Activation to Combat Proteotoxicity.Molecules (Basel, Switzerland) · 2019Review
- Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders.Journal of medicinal chemistry · 2019Review
- Methods to Discover and Evaluate Proteasome Small Molecule Stimulators.Molecules (Basel, Switzerland) · 2019Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Proteasome-mediated degradation of proteins is a vital cellular process and is performed by the ubiquitin-dependent proteasome system (UPS) and the ubiquitin-independent proteasome system (UIPS). While both systems are necessary to maintain healthy cell function, many disease states are characterized by reduced activity of the UPS, and the UIPS cannot by itself maintain proper protein levels. It has been suggested that the 20S core particle (20S CP), the isoform of the proteasome in the UIPS that can degrade proteins without a ubiquitin tag, can be stimulated with a small molecule to assist the 20S CP to accept and hydrolyze substrates more rapidly. Several small molecule stimulators of the 20S CP have since been discovered, including AM-404, an arachidonic acid derivative. AM-404 has previously been shown to inhibit fatty acid amide hydrolase activity. We wished to evaluate what structural components of AM-404 are required to stimulate the 20S CP with the long-term goal of using this information to design a stimulator with better drug-like qualities. We synthesized numerous derivatives of AM-404, varying the chain length, substitutions, and degree of unsaturation. Through this endeavor, we obtained several molecules capable of stimulating the 20S CP to various degrees. We discovered that though chain length is important, the presence of a cis-alkene in a specific location in the aliphatic chain has the greatest impact on the ability to stimulate the 20S CP. Two of the derivatives maintain modest stimulatory activity, and have improved toxicity over AM-404.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.