ArticleACS pharmacology & translational science2021
Macrocyclic Gq Protein Inhibitors FR900359 and/or YM-254890-Fit for Translation?
Article in ACS pharmacology & translational science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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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
20 citing papers in PubMed, 32 citations in OpenAlex.
- Small-molecule modulation of β-arrestins.Nature · 2026Article
- Molecular jackhammers induce intracellular calcium release and skeletal muscle contraction by vibronic-driven action.Chemical science · 2026Article
- Pharmacological Gq targeting prevents asthmatic airway remodeling.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- How residence time works in allosteric drugs.Current opinion in structural biology · 2025Review
- Allele-specific depletion ofMolecular therapy. Oncology · 2025Article
- Cyclic peptide inhibitors function as molecular glues to stabilize Gq/11 heterotrimers.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Gq/11 family of Gα subunits is necessary and sufficient for lower jaw development.Development (Cambridge, England) · 2025Article
- Rational Design of Ligands with Optimized Residence Time.ACS pharmacology & translational science · 2025Article
- Meeting Report From the 2023 Cure Ocular Melanoma (CURE OM) Global Science Meeting, Philadelphia, PA, November 2023.Pigment cell & melanoma research · 2025Article
- QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life.Journal of pharmacokinetics and pharmacodynamics · 2024Article
- Involvement of sphingosine 1-phosphate signaling in insulin-like growth factor-II/mannose 6-phosphate receptor trafficking from endosome to the trans-Golgi network.Communications biology · 2024Article
- Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy.Chemical science · 2024Article
- Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension.EMBO molecular medicine · 2024Article
- Plant peptides - redefining an area of ribosomally synthesized and post-translationally modified peptides.Natural product reports · 2024Review
- Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate GαACS pharmacology & translational science · 2023Review
- Article
- IGF1R Inhibition Enhances the Therapeutic Effects of Gq/11 Inhibition in Metastatic Uveal Melanoma Progression.Molecular cancer therapeutics · 2023Article
- Imaging of GαPharmaceutics · 2022Article
- Exploring pharmacological inhibition of GBritish journal of pharmacology · 2022Article
- Targeting Oncogenic GαCancers · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, G protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such as asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent selective inhibitors of the Gq subfamily of G proteins. FR and YM differ in two positions, FR being more lipophilic than YM. Both compounds are utilized as pharmacological tools to block Gq proteins in vitro and in vivo. However, no detailed characterization of FR and YM has been performed, which is a prerequisite for the compounds' translation into clinical application. Here, we performed a thorough study of both compounds' physicochemical, pharmacokinetic, and pharmacological properties. Chemical stability was high across a large range of pH values, with FR being somewhat more stable than YM. Oral bioavailability and brain penetration of both depsipeptides were low. FR showed lower plasma protein binding and was metabolized significantly faster than YM by human and mouse liver microsomes. FR accumulated in lung after chronic intratracheal or intraperitoneal application, while YM was more distributed to other organs. Most strikingly, the previously observed longer residence time of FR resulted in a significantly prolonged pharmacologic effect as compared to YM in a methacholine-induced bronchoconstriction mouse model. These results prove that changes within a molecule which seem marginal compared to its structural complexity can lead to crucial pharmacological differences.
Identifiers
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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.