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

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

Evolution-guided high yield production of potent Gαq/11-signalling inhibitors FR900359 and YM-254890. (PubMed, Metab Eng) - "Finally, duplication of FR900359 or YM-254890 BGCs in our newly developed host Δgbn::2attB further increased their titers to 177.9 and 29.2 mg/L (the highest yields reported to date), respectively. Collectively, our study paved the way for the cost-efficient, sustainable microbial production of both FR900359 and YM-254890, significantly facilitating the biotechnological application and drug development of the two potent Gαq/11-signalling inhibitors."

Journal • Oncology

Protease-activated receptor 1 as an endogenous model of peptidergic Gαq-Gα12-biased G protein signaling. (PubMed, Front Mol Biosci) - "Thrombin responses were suppressed by FR900359, supporting a requirement for Gαq in these platelet activation markers. Together, these findings support PAR1 as an endogenous model of protease-dependent functional selectivity that, in our heterologous assay systems, separates signaling along a Gαq-versus-Gα12 axis, thus providing a framework for future technologies, such as high-throughput tethered-peptide evolution platforms, to understand the principles of G protein selectivity across GPCRs."

Journal • ARRB1 • TGFA

Bosentan confers cardioprotection against cisplatin toxicity: Involvement of β-arrestin-linked ETA receptor signaling. (PubMed, Biochem Pharmacol) - "Inhibition of β-arrestin (barbadin) reduced bosentan's efficacy to a greater extent than Gαq protein inhibition (FR900359), highlighting a greater contribution of β-arrestin-mediated pathways. Although bosentan antagonizes both ETA and ETB receptors and modulates β-arrestin and Gαq signaling, its protective effect appears primarily mediated by ETA receptor antagonism and β-arrestin-linked pro-survival signaling. This potential mechanism of bosentan may provide a basis for further investigation into therapeutic strategies for chemotherapy-induced cardiotoxicity."

Journal • Cardiovascular • Metabolic Disorders • BCL2 • CASP3 • CASP7 • EDN1

Intercellular contact is sufficient to drive fibroblast-to-myofibroblast transitions. (PubMed, J Appl Physiol (1985)) - "Furthermore, we demonstrate that contact-based fibroblast-myofibroblast activation can be inhibited by the Gαq/11/14 inhibitor FR900359, which prevents the formation of myofibroblasts. These findings provide new insights into the persistence of the myofibroblast phenotype and highlight potential approaches to regulate the fibroblast-to-myofibroblast transition."

Journal • Fibrosis • Immunology

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

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

Protease-Activated Receptor 1 as an Endogenous Model of Peptidergic Gαq-Gα12-Biased G Protein Signaling. (PubMed, bioRxiv) - "Thrombin responses were suppressed by FR900359, supporting a Gαq requirement for these platelet activation markers. Together, these findings support PAR1 as an endogenous model of protease-dependent functional selectivity that, in our heterologous assay systems, separates signaling along a Gαq-versus-Gα12 axis, thus providing a framework for future technologies, such as high-throughput tethered-peptide evolution platforms, to understand the principles of G protein selectivity across GPCRs."

Journal • ARRB1 • TGFA

Multi-Targeting Non-Specific Genome Engineering in Bacteria. (PubMed, Adv Sci (Weinh)) - "Using MNGE, the fungicide UK-2 BGC (41 kb) and the polyether antibiotic salinomycin BGC (106 kb) were randomly integrated into a heterologous host Streptomyces albus, significantly enhancing their fermentation levels based on chromosome position effects. Furthermore, the potent Gq/11-signaling inhibitor FR900359 BGC (66 kb) was successfully expressed in Burkholderia gladioli by the MTI1 system. Together, the MNGE approach exhibits broad applicability for next-generation genome engineering in diverse bacteria, thereby achieving highly efficient production of high-value compounds."

Journal • Infectious Disease

Identification of strong constitutive promoters in Burkholderia stagnalis TBRC 18363 for activating natural product production in Gram-negative bacteria. (PubMed, Appl Microbiol Biotechnol) - "Promoter exchange experiments at biosynthetic gene clusters showed that these promoters can enhance the production titers of icosalide in B. stagnalis TBRC 18363 and FR900359, a Gq/11 protein inhibitor depsipeptide, in Chromobacterium vaccinii...• Efficiencies of the selected promoters were evaluated in two heterologous hosts. • p2035 and p5642 promoters boosted BGC expression in Burkholderia and Chromobacterium."

Journal • Infectious Disease

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

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

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