ArticleMolecular pharmacology2025
Discovery of RGS2-FBXO44 interaction inhibitors using a cell-based NanoBit assay.
Article in Molecular pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
1 citing paper in PubMed.
- Molecular insights into the comorbidity of vitamin K-dependent clotting factor deficiency and chondrodysplasia punctata.Journal of thrombosis and haemostasis : JTH · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
Abstract
Regulators of G protein signaling (RGS) proteins negatively regulate signaling through G protein-coupled receptors, and reduced RGS protein function is involved in numerous pathologies. However, therapeutic intervention is challenging, as RGS proteins lack druggable binding pockets and enzymatic activity. Instead, targeting mechanisms that control RGS protein expression show promise as an alternative. Pharmacological stabilization of RGS2 would be a feasible therapeutic strategy in pathologies associated with reduced RGS2 protein levels, such as hypertension, heart failure, and asthma. RGS2 is rapidly degraded through the ubiquitin-proteasomal system, and we recently identified the E3 ligase that recognizes RGS2. F-box Only Protein 44 (FBXO44) acts as the substrate recognition site for RGS2 in this E3 ligase complex, and we hypothesize that inhibiting the RGS2-FBXO44 interaction will lead to enhanced RGS2 levels. Here, we developed a NanoLuc Binary Technology (NanoBiT) assay that detects the interaction between RGS2 and FBXO44. This assay was used to screen 1600 compounds from the Life Chemicals protein-protein interaction fragment library. We identified a promising hit, denoted compound 10, that inhibits the RGS2-FBXO44 interaction with a potency of 19.6 μM, through direct binding to RGS2. The resulting increase in RGS2 protein levels is dependent on FBXO44, as siRNA-mediated FBXO44 knockdown attenuates the effect of compound 10. Altogether, compound 10 represents the first example of a small-molecule inhibitor of the RGS2-FBXO44 interaction and a first step toward the development of molecular probes with a defined mechanism to stabilize RGS2 protein levels. SIGNIFICANCE STATEMENT: This study provides a strategy to identify molecules that selectively inhibit RGS2 protein degradation as well as the first example of a compound with the ability to inhibit RGS2 interaction with the E3 ligase component FBXO44. This study provides proof of concept that a small-molecule RGS2-FBXO44 interaction inhibitor will increase RGS2 protein levels. Future development of compounds with this mechanism of action would be clinically useful in pathologies associated with low RGS2 protein levels, including hypertension, heart failure, and asthma.
Indexed as
Identifiers
What OpenQuestion holds
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.