YM-254890 / Astellas - LARVOL DELTA

TAS1R3 regulates GTPase signaling in human skeletal muscle cells for glucose uptake. (PubMed, bioRxiv) - "Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Galphaq/11 involvement was tested using YM-254890...TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Galphaq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D."

Journal • Metabolic Disorders • Type 2 Diabetes Mellitus • GNAQ • RAC1

GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice. (PubMed, Diabetologia) - "Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq-TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist."

Journal • Preclinical • Diabetes • GCG

The thiazolidinedione drug troglitazone inhibits Gq signaling through direct binding to the Gq alpha subunit through inhibition of GDP release. (PubMed, Mol Pharmacol) - "Previously discovered bacterial depsipeptides (FR900359 and YM-254890) bind directly to Gαq and stabilize its inactive complex with GDP, but suffer from limitations of distribution and bioavailability...The thiazolidinedione analogs, rosiglitazone and pioglitazone, had no effect...SIGNIFICANCE STATEMENT: Troglitazone, unlike other thiazolidinediones, directly binds and inhibits activity of heterotrimeric G protein Gq, with a weaker effect on Gi. Troglitazone may find usage as a repurposed drug scaffold to build novel small-molecule Gαq inhibitors with better bioavailability than depsipeptide Gαq inhibitors."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BRAF • GNAQ

Mycobacterium tuberculosis sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion. (PubMed, bioRxiv) - "These Ca²⁺ signals were attenuated by the Gαq/11 pathway inhibitor YM254890, even in the absence of extracellular Ca²⁺, suggesting involvement of intracellular Ca²⁺ stores. Together, these findings indicate that SL-1 engages Gαq/11-coupled pathways to sensitize nociceptors via intracellular Ca 2+ release, providing mechanistic insight into tuberculosis-associated cough and potential targets for therapeutic intervention."

Journal • Preclinical • Cough • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Tuberculosis • TRPV1

Pancreatic acinar cell signalling and function exhibit an absolute requirement for activation of Gαq. (PubMed, J Physiol) - "YM-254890 completely abrogates Ca2+-activated Cl- current activation, pivotal for fluid secretion together with amylase secretion stimulated by both M3R and CCK1R activation. We conclude that ACh and CCK stimulation results in Gq/11 activation, an increase in IP3 and DAG, and this event is fundamentally important for exocrine function."

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Cyclic peptide inhibitors function as molecular glues to stabilize Gq/11 heterotrimers. (PubMed, Proc Natl Acad Sci U S A) - "FR900359 (FR) and YM-254890 (YM), two natural cyclic peptides and highly specific inhibitors of Gq/11 heterotrimers, are exactly such tools. In doing so, they securely lock the entire heterotrimer, not just Gα, in its inactive state. Our results identify FR and YM as molecular glues for Gα and Gβγ that combine simultaneous binding to both subunits with inhibition of G protein signaling."

Journal • Targeted Protein Degradation

Gαq/11 Signaling Modulates Fibroblast Growth Factor 23 Production and Contributes to Acute Kidney Injury. (PubMed, FASEB J) - "This hypothesis was supported by using Gαq/11-specific inhibitors, YM-254890 and FR900359, which attenuated LPA-induced FGF23 upregulation. Moreover, in a folic acid-induced AKI mouse model, elevated FGF23 levels in bone, bone marrow, and serum were significantly reduced following YM-254890 administration, underscoring the potential of targeting Gαq/11 signaling in managing AKI-associated FGF23 dysregulation. This study not only advances our understanding of FGF23 regulation in renal injuries but also identifies Gαq/11 signaling modulation as a promising strategy to alleviate AKI severity and other disorders associated with dysregulated FGF23 levels."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • FGF23

Unveiling epigenetic mechanisms driving RasGRP3 upregulation via oncogenic Gαq signaling in uveal melanoma (AACR 2025) - "Treatment of UM cells with the Gαq inhibitor YM-254890 (YM) or the PKC inhibitor LXS-196 (LXS) for 24 hours significantly reduced all three histone modifications (H3K4me3, H3K27ac, H3K4me1) at the RasGRP3 locus. Ongoing investigations aim to delineate the precise mechanisms by which Gαq signaling drives these epigenetic changes. Our results highlight the potential of targeting specific histone modifiers as a novel therapeutic strategy for UM treatment."

Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ

MAPK Signaling and Angiopoietin-2 Contribute to Endothelial Permeability in Capillary Malformations. (PubMed, bioRxiv) - "The combination of ANGPT2 knockdown and Trametinib significantly restored the EC barrier to near EC-WT levels...The weakened endothelial barrier in the mutant ECscan be rescued by Gαq inhibitor, YM254890, confirming the compromised barrier is a consequence of the mutant Gαq...Currently there are no molecularly targeted therapies for non-syndromic CM or SWS. Our study shows the involvement of MAPK pathway and the proinflammatory molecule ANGPT2 in endothelial permeability and suggests a path to target GNAQ p.R183Q driven CM."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Glaucoma • Ophthalmology • GNAQ

The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890. (PubMed, J Biol Chem) - "Pulldown and BRET assays with the RGS-homology domain of GRK2, which can only bind activated αq, further demonstrated that Ric-8A expression enhances activation of αq, its ability to bind effectors, and therefore its ability to signal. With the understanding of YM acting as a GDI, we propose that Ric-8A hinders YM inhibitory effects by promoting GTP-bound, activated αqQL/P."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

The G protein inhibitor YM-254890 is an allosteric glue. (PubMed, J Mol Biol) - "This allostery gives rise to positive cooperativity, wherein the presence of Gβγenhances preorganization for YM binding. We predict that YM acts as an "allosteric" glue that allosterically stabilizes the complex between Gαand Gβγ despite the minimal contacts between YM and Gβγ."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

The antitumor effects of metformin are potentially mediated through LPA receptor inhibition. (PubMed, Diabetes Res Clin Pract) - "These results indicate that the inhibition of LPA receptor signaling by metformin, especially the consequent suppression of LPAR3-mediated cell migration, may contribute to the antitumor effects of metformin."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • EGF • LPAR3

Midnolin gene expression is enhanced by Gq-coupled muscarinic acetylcholine receptor stimulation in SH-SY5Y human neuroblastoma cells. (PubMed, J Pharmacol Sci) - "These effects were suppressed by atropine and a Gq inhibitor, YM254890, indicating that muscarinic receptor/Gq signaling is required for the induction of MIDN by acetylcholine. Our findings suggest that drugs that upregulate MIDN may have therapeutic potential for PD."

Journal • CNS Disorders • CNS Tumor • Movement Disorders • Neuroblastoma • Oncology • Parkinson's Disease • Solid Tumor

Local urothelial cell-driven detrusor contractions. (PubMed, bioRxiv) - "Nifedipine, which blocks extracellular Ca 2+ entry, abolished the contractions. G protein-coupled receptor inhibitor YM-254890 significantly inhibited the contractions. Hemichannel inhibitor carbenoxolone disodium and the exocytotic pathway of transmitter release inhibitor brefeldin A also showed significant inhibition of the contractions. In conclusion, we validated the previous hypothesis that urothelial release factors can influence bladder contractions locally without the need for signaling from the central nervous system. Further studies are needed to determine the relevance of this signaling pathway in normal bladder physiology and pathophysiologic conditions."

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A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C. (PubMed, Purinergic Signal) - "We and others reported that Gαq/11 inhibitor FR900359 (FR) can inhibit both Gαq- and, surprisingly, Giβγ-mediated intracellular Ca2+ mobilization...However, in T24 bladder cancer cells, Gi inhibitor PTX, but not Gαq/11 inhibitors, FR, YM254890 (YM) or Gq/11 siRNA, inhibited Ca2+ increase triggered by native A2BAR activation...Thus, Gαq/11 is vital for Ca2+ increase in some cell types, but Giβγ-mediated Ca2+ signaling can be Gαq/11-dependent or independent based on cell type and receptor activated. Besides G proteins, PKC also modulates cytosolic Ca2+ increase depending on cell type and receptor."

Journal • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • ARRB1

A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C. (PubMed, Res Sq) - "However, in T24 bladder cancer cells, G i inhibitor PTX, but not G αq/11 inhibitors, FR, YM254890 (YM) or G q/11 siRNA, inhibited Ca 2+ increase triggered by native A 2B AR activation...Thus, G αq/11 is vital for Ca 2+ increase in some cell types, but G iβγ -mediated Ca 2+ signaling can be Gα q/11 -dependent or independent based on cell type and receptor activated. Besides G proteins, PKC also modulates cytosolic Ca 2+ increase depending on cell type and receptor."

Journal • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • ARRB1

The G protein inhibitor YM-254890 is an allosteric glue. (PubMed, bioRxiv) - "This allostery gives rise to positive cooperativity, wherein the presence of Gβγ enhances preorganization for YM binding. We predict that YM acts as an "allosteric" glue that allosterically stabilizes the complex between Gα and Gβγ despite the minimal contacts between YM and Gβγ."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Diverse pathways in GPCR-mediated activation of Ca2+ mobilization in HEK293 cells. (PubMed, J Biol Chem) - "β-agonist-promoted Ca2+ mobilization was effectively blocked by the Gq-selective inhibitor YM-254890 and was not observed in ΔGαq/11 or ΔPLCβ cells...Interestingly, both EP2R and EP4R were largely unable to induce Ca2+ mobilization in ΔGαs or ΔPLCβ cells, supporting a strong dependency on Gs signaling in HEK293 cells. Taken together, we identify differences in the signaling pathways that are utilized to mediate Ca2+ mobilization in HEK293 cells where the β2AR primarily utilizes Gq, EP2R uses Gs and Gi, and EP4R utilizes Gs, Gi and Gq."

Journal • Infectious Disease • Respiratory Diseases • PTGER4

Stabilization of interdomain closure by a G protein inhibitor. (PubMed, Proc Natl Acad Sci U S A) - "Epitomizing this approach are YM-254890 (YM) and FR900359 (FR), which are efficacious in models of thrombosis, hypertension, obesity, asthma, uveal melanoma, and pain, and under investigation as an FR-antibody conjugate in uveal melanoma clinical trials. All three classes of mammalian Gα subunits that are insensitive to YM/FR possess homologous but degenerate YM/FR binding sites, yet can be inhibited upon transplantation of the YM/FR binding site of Gq. Novel YM/FR analogs tailored to each class of G protein will provide powerful new tools for therapeutic investigation."

Journal • Asthma • Cardiovascular • Eye Cancer • Genetic Disorders • Hematological Disorders • Hypertension • Immunology • Melanoma • Obesity • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombosis • Transplantation • Uveal Melanoma

Ghrelin modulates voltage-gated Ca2+ channels through voltage-dependent and voltage-independent pathways in rat gastric vagal afferent neurons. (PubMed, Mol Pharmacol) - "We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca2+ current inhibition was mediated by Gαi/o or Gαq/11 family of subunits...Significance Statement This study demonstrated that in gastric vagal afferent neurons, activation of GHSR1a by ghrelin inhibits voltage-gated Ca2+ channels through both voltage-dependent and voltage-independent signaling pathways. These results provide necessary insight into the cellular mechanism underlying ghrelin regulation of gastric vagal afferent activity, which may benefit future studies investigating ghrelin mimetics to treat gastric motility disorders."

Journal • Preclinical • Gastrointestinal Disorder • Infectious Disease • Respiratory Diseases

Differential epitope tagging of oncogenic GNAQ mutants produces distinct effects on downstream signaling of GNAQ (AACR 2024) - "These data suggest that EE tag has no effect on the function of GNAQ , but interfereswith YM-254890 binding. Our findings highlight unappreciated consequences of epitope-tagging of the oncogene GNAQ that are relevant for studies on the interactome of mutant GNAQ and drug response."

Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ

Intracellular pathways of calcitonin gene-related peptide-induced relaxation of human coronary arteries: A key role for Gβγ subunit instead of cAMP. (PubMed, Br J Pharmacol) - "While CGRP signalling is generally assumed to act via cAMP, the CGRP-induced vasodilation in HCA was not inhibited by targeting this intracellular signalling pathway at different levels. Instead, inhibition of Gβγ subunits did inhibit the relaxation to CGRP, suggesting a different mechanism of CGRP-induced relaxation than generally believed."

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Histamine H1 Receptor-Mediated JNK Phosphorylation Is Regulated by Gq Protein-Dependent but Arrestin-Independent Pathways. (PubMed, Int J Mol Sci) - "Histamine-induced JNK phosphorylation in CHO cells expressing WT and S487TR was suppressed by inhibitors against H1 receptors (ketotifen and diphenhydramine), Gq proteins (YM-254890), and protein kinase C (PKC) (GF109203X) as well as an intracellular Ca2+ chelator (BAPTA-AM) but not by inhibitors against G protein-coupled receptor kinases (GRK2/3) (cmpd101), β-arrestin2 (β-arrestin2 siRNA), and clathrin (hypertonic sucrose). These results suggest that the H1 receptor-mediated phosphorylation of JNK is regulated by Gq-protein/Ca2+/PKC-dependent but GRK/arrestin/clathrin-independent pathways."

Journal • Inflammation • ARRB1 • MAPK8

In Vitro Module Editing Of NRPS Enables Production Of Highly Potent Gq-Signaling Inhibitor FR900359 Derived From Unculturable Plant Symbiont. (PubMed, Angew Chem Int Ed Engl) - "We therefore embarked on constructing an artificial biosynthetic gene cluster (BGC) for FR900359 with YM-254890 BGC as a template using "in vitro module editing" technology, first developed for the modification of type-I PKS BGCs, to edit YM-254890 BGC. The resulting artificial BGCs coding FR900359 were heterologously expressed in the Pseudomonas putida KT2440 host strain."

Journal • Preclinical

A Building Block Approach for the Total Synthesis of YM-385781. (PubMed, European J Org Chem) - "YM-254890 and FR900359 are potent and selective inhibitors of the Gq/11-signaling pathway. Yet in spite of this effort, a versatile synthetic approach to the molecules that allows for the rapid construction of a variety of non-natural and labelled analogs and an increase in the amount of those analogs available remains elusive. We report here a convergent building block approach to the molecules that can solve this challenge."

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