FR900359 / Sidney Kimmel Cancer Center, Thomas Jefferson University, Icahn School of Medicine at Mount Sinai, Astellas - LARVOL DELTA

In silico Discovery of Novel Small-Molecule Inhibitors Targeting Oncogenic GNAQ/GNA11 Mutations in Uveal Melanoma (ESSO 2025) - "For dose-response assays, a reference compound (FR900359), which locks G⍺q in its inactive guanosine diphosphate (GDP)-bound state, was included and demonstrated expected inhibitory activity in UM cell lines...Conclusions (For surgical proposals, write down NA) This study highlights the potential of in silico drug discovery to target G⍺q-driven signaling in UM. Although functional validation is ongoing, these findings lay the groundwork for systematic preclinical evaluation of small molecules targeting UM via G⍺q inhibition."

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

Analysis of flavonoid glucosides from Ardisia and Damnacanthus spp. using UPLC-DAD-QToF/mS. (PubMed, Nat Prod Res) - "In order to investigate the compositional characteristics of leaves and fruits from Ardisia crenata, source of the potent Gq inhibitor FR900359, as well as leaves of other related Ardisia and rarely investigated Damnacanthus species, we report the structural identification and quantification of flavonoid glycosides from these plants...A total of forty-six flavonoid glycosides were identified and their quantitative results based on the internal standard, 2,4,5-trimethoxycinnamic acid, are reported for the first time. Also, among these samples, the leaves of the red fruit Ardisia crenata showed the highest content of 20 types of flavonoids including kaempferol 3-O-glucoside (astragalin), at 503.8 ± 11.9 mg/100 g."

Journal

Pharmacological Gq targeting prevents asthmatic airway remodeling. (PubMed, Mol Ther) - "We have investigated this pathological process and found that local application of the pharmacological Gq inhibitor FR900359 (FR) attenuates the main features of airway remodeling, namely collagen deposition and goblet cell metaplasia in the chronic ovalbumin-induced asthma model in mouse...Notably, FR blocks mucus secretion in human lung slices from asthmatic patients. Thus, Gq proteins play a critical role in airway remodeling, hence pharmacological inhibition of Gq signaling represents a promising strategy for the treatment of chronic asthma."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

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

A first-in-human study of DYP688, an antibody drug conjugate delivering a direct Gq/11 inhibitor, in patients with metastatic uveal melanoma (MUM) and other GNAQ/11 mutant melanomas. (ASCO 2025) - P1/2 | "SDZ475 (FR900359) is a potent GNAQ/11 inhibitor, however in vivo toxicity has precluded clinical development...Of the 66 treated pts, 60 (90.9%) had prior antineoplastic therapy; 38 (57.6%) received ≥2 lines, and 22 (33.3%) received prior tebentafusp... DYP688 shows favorable safety and tolerability at all doses tested and promising preliminary clinical efficacy at doses ≥ 12mg/kg Q2W; the RDs for dose optimization are yet to be declared and dose exploration is ongoing."

Clinical • Metastases • P1 data • Anemia • Endocrine Disorders • Eye Cancer • Fatigue • Hematological Disorders • Hypotension • Melanoma • Metabolic Disorders • Oncology • Solid Tumor • Uveal Melanoma • Xerostomia • GNAQ • PMEL

Silencing Gq Proteins Prevents and Reverses Pulmonary Hypertension (ATS 2025) - "Therefore, we analyzed the potential of the specific pan-Gq inhibitor FR900359 (FR) to modulate pulmonary vascular tone and remodeling; in addition, we evaluated the contribution of Gαq and Gα11 to the pathophysiology of PH using the respective knockout (KO) mice...After ET-1 pre-constriction in mouse PAs, the vasodilatory effect of FR was superior to the relaxation in response to currently used drugs such as the ET-1 receptor antagonist bosentan, the prostacyclin analog iloprost or the phosphodiesterase 5 inhibitor sildenafil...Thus, we show that the pharmacological Gq inhibitor FR counteracts the main hallmarks of PH and that these are predominantly Gαq-driven. Therefore, Gq proteins, especially Gαq, could be a promising therapeutic target for PH in the future."

Late-breaking abstract • Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EDN1

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

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

QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life. (PubMed, J Pharmacokinet Pharmacodyn) - "DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm."

Journal • Oncology

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

Structural response of G protein binding to the cyclodepsipeptide inhibitor FR900359 probed by NMR spectroscopy. (PubMed, Chem Sci) - "This revealed rigidification of the switch I binding site and an allosteric response in the α5 helix as well as suppression of structural changes induced by nucleotide exchange due to inhibition by FR. Our NMR studies of the FR-G protein complex conducted directly within a native membrane environment provide important insights into the inhibitors access via the lipid membrane, binding mode, and structural allosteric effects."

Journal

Condensation domain editing of the FR900359 assembly line yields a novel analog amenable to late-stage functionalization. (PubMed, Chembiochem) - "Options for late-stage functionalization of FR are limited due to a lack of tractable functional groups. Here we present a mixed approach combining i) genetic engineering of the FR-assembly line in Chromobacterium vaccinii, to obtain a novel FR analog featuring a primary amine, with ii) its subsequent synthetic modification and biological profiling for further SAR exploration of the FR scaffold."

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

Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension. (PubMed, EMBO Mol Med) - "We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo...We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Decoding the molecular mechanisms related to mutations in the GNAQ/11 and BAP1 genes in ocular melanoma (AACR 2024) - "Finally, in vitro testing has been started for inhibitors targeting compensatory pathways involving beta-catenin (WIKI4) and ERK1/2 (ASN007), in combination with the GNAQ/11 inhibitor (FR900359). These tests are being conducted on various mutant UMCCs for GNAQ/11.A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically UM cells."

Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • CTNNB1 • GNA11 • GNAQ

ABCB1 promotes uveal melanoma cell resistance to FR900359 and identifies a tumor cell subpopulation with a distinct gene expression signature (AACR 2024) - "Ongoing RNA-sequencing analysis from PDVT samples has identified distinct gene expression signatures associated with FR treatment and ABCB1 expression. These findings are expected to illuminate tumor cell heterogeneity amongst UM cell populations that may be related to drug resistance and metastasis."

Clinical • Tumor cell • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • ABCB1 • GNA11 • GNAQ

Decoding the molecular mechanisms related to mutations in the GNAQ/11 and BAP1 genes in ocular melanoma (AACR 2024) - "Finally, in vitro testing has been started for inhibitors targeting compensatory pathways involving beta-catenin (WIKI4) and ERK1/2 (ASN007), in combination with the GNAQ/11 inhibitor (FR900359). These tests are being conducted on various mutant UMCCs for GNAQ/11.A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically UM cells."

Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • CTNNB1 • GNA11 • GNAQ

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."

Journal

Recommended Tool Compounds: Application of YM-254890 and FR900359 to Interrogate Gα-Mediated Signaling Pathways. (PubMed, ACS Pharmacol Transl Sci) - "Yet, the possibilities to interrogate Gα signaling in complex systems have only been exploited in a very limited number of studies, whose promising initial results warrant further application of YM and FR in basic and translational research. As both compounds have become commercially available as of late, this review focuses on their application in cell-based assays and in vivo systems, highlighting their qualities as tool compounds and providing instructions for their use."

Journal • Review • Cholera • Infectious Disease • Respiratory Diseases

Protein kinase signaling networks driven by oncogenic Gq/11 in uveal melanoma identified by phosphoproteomic and bioinformatic analyses. (PubMed, Mol Cell Proteomics) - "We used the highly specific Gq/11 inhibitor FR900359 (FR) to elucidate signaling networks that drive proliferation, metabolic reprogramming, and dedifferentiation of UM cells...ssGSEA, unsupervised analysis, and functional studies indicated that mTORC1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) drive metabolic reprogramming in UM cells. Together, these results identified protein kinase signaling networks driven by oncogenic Gq/11 that regulate critical aspects of UM cell biology and provide targets for therapeutic investigation."

Journal • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CDK1 • CDK2 • GNA11 • GNAQ

Identification of 2,4-diacetylphloroglucinol production in the genus Chromobacterium. (PubMed, Sci Rep) - "We also confirmed the ability of C. vaccinii strains to produce bioactive pigment violacein and bioactive cyclic depsipeptide FR900359. Both compounds have been reported to have antimicrobial and insecticidal activities. These compounds suggest strains of C. vaccinii should be further explored for their potential as biocontrol agents."

Journal • Gene Therapies

The Bacterial G Signal Transduction Inhibitor FR900359 Impairs Soil-Associated Nematodes. (PubMed, J Chem Ecol) - "Finally, egg-laying of C. elegans and hatching of juvenile stage 2 of H. schachtii from its cysts is inhibited by FR, suggesting that FR might reduce nematode dispersion and proliferation. This study supports the idea that C. vaccinii and its excreted metabolome in the soil might contribute to an ecological equilibrium, maintaining and establishing the successful growth of plants."

Journal

Adenylation Domain-Guided Recruitment of Trans-Acting Nonheme Monooxygenases in Nonribosomal Peptide Biosynthesis. (PubMed, ACS Chem Biol) - "Here, we report the crystal structure of FrsH, the NHDM which catalyzes the β-hydroxylation of l-leucines during biosynthesis of the depsipeptide G protein inhibitor FR900359...FrsH can be functionally substituted by homologous enzymes from biosyntheses of the cell-wall-targeting antibiotics lysobactin and hypeptin, indicating that these features are generally applicable to members of the family of trans-acting NHDMs. These insights give important directions for the construction of artificial assembly lines to yield bioactive and chemically complex peptide products."

Journal

Real-time detection of bind events between YM/FR analogs and G proteins on the microelectrode array (ACS-Fall 2023) - "YM-254890 and FR900359 are selective Gq/11-signaling pathway inhibitors, and they have been attractive targets for both synthesis and biological studies. To understand the origin of their selective binding activity, we discussed a powerful method to detect the binding activity between YM/FR analogs and G proteins in real-time by taking advantage of microelectrode array. To make the analogs, a versatile synthetic approach with building block strategy is also discussed."