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Glumetinib (SCC244; SCC-244; Gumarontinib) is a novel, potent and highly selective c-Met kinase inhibitor (IC50 = 0.42 nM.) with antitumor activity. Remarkably selective compared to 312 other tested protein kinases, glumetinib demonstrated subnanomolar potency against c-Met kinase activity. This makes it one of the most selective c-Met inhibitors currently available. Additionally, the c-Met-dependent neoplastic phenotype of tumor and endothelial cells is suppressed by this inhibitor, which profoundly and specifically inhibits c-Met signal transduction.
Physicochemical Properties
| Molecular Formula | C21H17N9O2S |
| Molecular Weight | 459.4838 |
| Exact Mass | 459.12 |
| Elemental Analysis | C, 54.89; H, 3.73; N, 27.44; O, 6.96; S, 6.98 |
| CAS # | 1642581-63-2 |
| Related CAS # | 1642581-63-2 |
| PubChem CID | 117797905 |
| Appearance | White to off-white solid powder |
| LogP | 1.9 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 33 |
| Complexity | 825 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | RYBLECYFLJXEJX-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H17N9O2S/c1-27-11-16(7-24-27)14-3-4-20-23-10-21(29(20)13-14)33(31,32)30-19-5-15(6-22-18(19)9-26-30)17-8-25-28(2)12-17/h3-13H,1-2H3 |
| Chemical Name | 6-(1-methylpyrazol-4-yl)-1-[6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]sulfonylpyrazolo[4,3-b]pyridine |
| Synonyms | SCC-244; SCC244; SCC 244; Gumarontinib. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
c-Met kinase (IC50 = 0.42 nM) c-Met kinase (IC₅₀ = 0.42 ± 0.02 nmol/L) >2,400-fold selectivity for c-Met over 312 other kinases, including RON, Axl, Mer, and TyrO3 [1] |
| ln Vitro |
SCC244 significantly inhibits the phosphorylation of c-Met, AKT, and ERK in EBC-1, MKN-45 cells with an amplified MET gene, and HGF-stimulated U87MG cells. SCC244 inhibits the proliferation of cancer cells driven by c-Met in a targeted and effective manner. It suppresses angiogenesis and metastasis, two c-Met-dependent neoplastic phenotypes[1]. SCC244 potently inhibits c-Met phosphorylation and downstream AKT/ERK signaling in MET-amplified (EBC-1, MKN-45) and HGF-stimulated (U87MG) cells, as well as in BaF3/TPR-Met cells expressing a constitutively active c-Met rearrangement [1] SCC244 selectively inhibits proliferation of c-Met-addicted cancer cell lines (EBC-1, MKN-45, SNU-5, BaF3/TPR-Met) with IC₅₀ values ranging from 0.86 to 2.4 nmol/L, while showing ~10,000-fold lower potency in cells with low c-Met expression/activation [1] SCC244 induces G₁–S phase cell cycle arrest in c-Met-addicted cells [1] SCC244 inhibits HGF-induced migration and invasion of NCI-H441 cells in a dose-dependent manner [1] SCC244 inhibits HGF-induced scattering and branching morphogenesis of MDCK cells, reflecting inhibition of invasive growth [1] SCC244 inhibits HGF-stimulated c-Met signaling and proliferation in primary HUVECs (IC₅₀ = 8.8 ± 0.4 nmol/L) [1] |
| ln Vivo |
SCC244 administration shows strong antitumor activity at well-tolerated doses in xenografts of human tumor cell lines, non-small cell lung cancer, and hepatocellular carcinoma patient-derived tumor tissue driven by MET aberration. SCC244 also inhibits c-Met downstream signaling through a mechanism of combined antiproliferation and antiangiogenic effects, which contributes to its in vivo antitumor activity[1]. SCC244 (2.5–10 mg/kg, oral, once daily) significantly inhibits tumor growth in MET-amplified CDX models (MKN-45, SNU-5, EBC-1), inducing tumor stasis or regression [1] SCC244 reduces tumor Ki67 expression and intratumoral microvessel density (CD31 staining) in xenograft models [1] SCC244 decreases plasma levels of pro-angiogenic factor IL-8 in xenograft models [1] SCC244 shows robust antitumor activity in MET-aberrant NSCLC and HCC PDX models at 10 mg/kg, with tumor growth inhibition ranging from 87.7% to 115.8% [1] SCC244 induces complete or partial responses in several PDX models, including complete responses in LU2503 and LI0612 models [1] |
| Enzyme Assay |
c-Met kinase activity was assessed using ELISA and radiometric protein kinase assays. SCC244 was tested against purified c-Met kinase, and IC₅₀ was determined. ATP competition assays were performed with varying ATP concentrations to confirm competitive inhibition [1] Kinase selectivity profiling was performed against a panel of 312 kinases using radiometric assays at 1 μmol/L SCC244 [1] |
| Cell Assay |
Prior to a 2-hour treatment with SCC244 and a 15-minute HGF stimulation period, U87MG cells are serum-deprived for a full day. Once the cells are lysed, a Western blot analysis is performed. Cell proliferation assays were performed using sulforhodamine B, MTT, or CCK-8 assays. Cells were seeded in 96-well plates, treated with compounds for 72 hours (48 hours for HUVECs with HGF stimulation), and viability was measured [1] For cell cycle analysis, cells were treated with compounds for 24 hours, fixed, stained with propidium iodide, and analyzed by flow cytometry [1] Migration and invasion assays used Transwell plates (8 μm pores) with or without Matrigel coating. Cells were seeded in serum-free medium, and HGF was added to the lower chamber. After 24 hours, migrated/invaded cells were fixed, stained, and quantified [1] MDCK scattering assay: cells were treated with HGF and compounds for 24 hours, fixed, and stained [1] MDCK branching morphogenesis assay: cells were embedded in collagen I gel, treated with HGF ± compounds, and imaged after 5 days [1] |
| Animal Protocol |
Female nude mice with xenograft tumors 10 mg/kg oral For CDX models, tumor fragments (~1 mm³) from established subcutaneous tumors were transplanted into nude mice. When tumor volume reached 100–150 mm³, mice were randomized into groups and treated orally once daily with SCC244 or vehicle for 2–3 weeks. Tumor volume was measured twice weekly [1] For PDX models, NSCLC and HCC patient-derived tumors were implanted in mice. When tumors reached 100–200 mm³, mice were treated orally once daily with SCC244 (10 mg/kg) or vehicle for 18–21 days [1] Tumor volume = (length × width²) / 2. Tumor growth inhibition (TGI) was calculated as 100 × {1 − [(V_treated_final − V_treated_day0) / (V_control_final − V_control_day0)]} [1] |
| Toxicity/Toxicokinetics |
In preclinical studies, SCC244 was well tolerated with no significant body weight loss even at 50 mg/kg in mice [1] In a 28-day repeated-dose study in rats, the NOEL was 10 mg/kg/day, and MTD was >100 mg/kg/day. Mild reversible increases in WBC were observed at higher doses [1] In a 28-day repeated-dose study in dogs, the NOAEL was 5 mg/kg/day, and MTD was 60 mg/kg/day. Reversible ECG changes, GI effects, thymic lymphoid atrophy, and bone marrow changes were noted at higher doses [1] Therapeutic index (MTD / tumor stasis dose) was >40 in both rats and dogs [1] |
| References |
[1]. Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models. Mol Cancer Ther. 2018 Apr;17(4):751-762. |
| Additional Infomation |
Glumetinib is under investigation in clinical trial NCT04270591 (Assess the Anti-tumor Activity and Safety of Glumetinib in Patient With Advanced C-met-positive Non-small Cell Lung Cancer). Gumarontinib is an orally bioavailable, small molecule inhibitor of the oncoprotein c-Met (hepatocyte growth factor receptor; HGFR), with potential antineoplastic activity. Upon oral administration, gumarontinib targets and binds to the c-Met protein, thereby disrupting c-Met-dependent signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. c-Met protein is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. SCC244 is an oral, potent, and highly selective c-Met inhibitor with subnanomolar biochemical and nanomolar cellular potency [1] It inhibits c-Met signaling and c-Met-dependent neoplastic phenotypes including proliferation, migration, invasion, and angiogenesis [1] It shows robust antitumor activity in MET-dependent xenograft models with a favorable preclinical safety profile [1] It received CFDA IND approval in January 2017 and entered Phase I clinical trials [1] |
Solubility Data
| Solubility (In Vitro) | DMSO: 11~41.7 mg/mL (23.9~90.7 mM) |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1764 mL | 10.8819 mL | 21.7637 mL | |
| 5 mM | 0.4353 mL | 2.1764 mL | 4.3527 mL | |
| 10 mM | 0.2176 mL | 1.0882 mL | 2.1764 mL |