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Purity: ≥98%
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.
| 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] |
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| 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 weight loss observed even at doses up to 50 mg/kg in mice [1]. In a 28-day repeated-dose study in rats, the no adverse effect level (NOEL) was 10 mg/kg/day, and the maximum tolerated dose (MTD) was > 100 mg/kg/day. Mild reversible leukocyte count elevation was observed at high doses [1]. In a 28-day repeated-dose study in dogs, the no adverse effect level (NOAEL) was 5 mg/kg/day, and the maximum tolerated dose (MTD) was 60 mg/kg/day. Reversible ECG changes, gastrointestinal reactions, thymic lymphoid tissue atrophy, and bone marrow changes were observed at high doses [1]. In both rats and dogs, the treatment index (maximum tolerated dose/tumor inhibitor dose) was > 40 [1].
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| References | |
| Additional Infomation |
Glumetinib is being studied in the clinical trial NCT04270591 (evaluating the antitumor activity and safety of glutmetinib in patients with advanced c-Met-positive non-small cell lung cancer). Glumetinib is a small molecule c-Met (hepatocyte growth factor receptor; HGFR) oncoprotein inhibitor with high oral bioavailability and potential antitumor activity. After oral administration, glutmetinib targets and binds to c-Met protein, thereby blocking c-Met-dependent signal transduction pathways. This may induce death in tumor cells that overexpress c-Met protein or express constitutively activated c-Met protein. c-Met protein is overexpressed or mutated in a variety of tumor cell types and plays a key role in tumor cell proliferation, survival, invasion, metastasis and tumor angiogenesis. SCC244 is an oral, highly effective and selective c-Met inhibitor with sub-nanomolar biochemical potency and nanomolar cellular potency [1]. It inhibits the c-Met signaling pathway and c-Met-dependent tumor phenotypes, including proliferation, migration, invasion, and angiogenesis[1]. It has shown strong antitumor activity in MET-dependent xenograft models and good preclinical safety[1]. It received CFDA IND approval in January 2017 and entered Phase I clinical trials[1].
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| Molecular Formula |
C21H17N9O2S
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|---|---|
| Molecular Weight |
459.4838
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| Exact Mass |
459.12
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| Elemental Analysis |
C, 54.89; H, 3.73; N, 27.44; O, 6.96; S, 6.98
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| CAS # |
1642581-63-2
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| Related CAS # |
1642581-63-2
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| PubChem CID |
117797905
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| Appearance |
White to off-white solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
33
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| Complexity |
825
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RYBLECYFLJXEJX-UHFFFAOYSA-N
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| 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
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| 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
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| Synonyms |
SCC-244; SCC244; SCC 244; Gumarontinib.
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 11~41.7 mg/mL (23.9~90.7 mM)
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04270591 | Recruiting | Drug: Glumetinib | C-Met Exon 14 Mutation | Haihe Biopharma Co., Ltd. | July 15, 2019 | Phase 1 Phase 2 |
| NCT05507294 | Completed | Drug: Glumetinib | Healthy Volunteers | Haihe Biopharma Co., Ltd. | March 2, 2021 | Phase 1 |
| NCT04797702 | Completed | Combination Product: Glumetinib combined with Toripalimab |
Relapsed or Metastatic Non- small Cell Lung Cancer |
Shanghai Junshi Bioscience Co., Ltd. |
April 15, 2021 | Phase 1 Phase 2 |
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