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Famitinib (SHR-1020) is a novel and potent multi-targeted receptor tyrosine kinase/RTK inhibitor with anticancer activity. It is being developed for cancer treatment, phase II clinical trials in China for the treatment of renal cell carcinoma, gastrointestinal stromal tumours, pancreatic cancer, and nasopharyngeal carcinoma.
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| ln Vitro |
Famitinib reduces microvascular eruption in rat aortic rings implanted in Matrigel, as well as VEGF-induced proliferation, migration, and tubule formation of human umbilical vein endothelial cells [1]. Famitinib (1.8 and 3.6 μM; 48 h) induces apoptosis in a dose-dependent manner and causes cell cycle arrest in the G2/M phase, which suppresses cell proliferation in gastric cancer cell lines [2]. In a dose-dependent manner, fuminib (0.6 -20.0 μM; 24-72 h) suppresses the development of stomach cancer cells [2].
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| ln Vivo |
Several well-established xenografts made from human tumor cell lines experience regression or growth arrest when exposed to fumitinib, which has extensive and strong anticancer activity [1]. By preventing angiogenesis, mitinib (50 and 100 mg/kg; po once daily for 3 weeks) slows the growth of tumors in vivo [2].
In vivo, famitinib exhibited broad and potent anti-tumor activity, leading to regression or growth arrest of various established xenografts derived from human tumor cell lines. Moreover, famitinib significantly enhanced the efficacy of oxaliplatin or 5-fluorouracil when they were combined. In summary, famitinib has potent preclinical antitumor activity which supports its further evaluation in clinic. Famitinib is currently in phase I clinical trials in China[1]. |
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| Enzyme Assay |
Famitinib inhibited the activity of c-kit, VEGFR-2, PDGFRα and PDGFRβ with IC50 values of 2.3 nM, 4.7 nM and 6.6 nM, respectively. In addition, Famitinib inhibited the VEGF-induced proliferation, migration and tubule formation of human umbilical vein endothelial cells, and micro-vessel spouting from matrigel-embedded rat aortic rings.[1]
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay Cell apoptosis was measured via TUNEL assay according to the manufacturer's protocol. Upon treatment of the cells with famitinib for 48 h, cells were washed with phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde for 10 min at room temperature. Cells were then stained with the corresponding reagents provided in the TUNEL assay kit. Upon overlaying the coverslips, slides were imaged under fluorescence microscopy. Positive cells exhibited green fluorescence and were counted from three random microscopic fields[2]. |
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| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: Human gastric cancer cells BGC-823 and MGC-803 Tested Concentrations: 0, 0.6, 1.25, 2.5, 5.0, 10.0 and 20.0 µM Incubation Duration: 24, 48 and 72 hrs (hours) Experimental Results: Inhibited cell growth in a dose-dependent manner with IC50 values of 3.6 and 3.1 µM for BGC-823 and MGC-803 cells, respectively. |
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| Animal Protocol |
Animal/Disease Models: 18-20 g female BALB/c athymic nu/nu (nude) mice (age, 6–8 weeks) bearing BGC-823 xenografts[2]
Doses: 50 and 100 mg/kg Route of Administration: po (oral gavage); 50 and 100 mg/ kg; one time/day for 3 weeks Experimental Results: Inhibited BGC-823 xenograft growth (tumor volume, 395.2 vs. 2,690.5 mm3), and animal weights were similar between groups (21.6 vs. 18.7 g). In vivo xenograft model experiments BGC-823 cells were suspended in PBS (1×107 cells/ml), and 100 µl of the cell suspension was subcutaneously injected into the right axillary area of 18-20-g female BALB/c athymic nu/nu mice (n=40; age, 6–8 weeks). The temperature of the housing conditions was maintained at 23–25°C with a humidity of 50–60% and a 10/14 h light/dark cycle. Food and water were changed 3 times a week. When the tumor volume reached ~100 mm3, mice were randomized into treatment groups. Tumors and animal weights were measured twice weekly, and tumor volume was calculated using the following formula: V=LxW2x1/2 (where V represents tumor volume, L is the length of the tumor and W is the width of the tumor). To measure famitinib, three groups were randomized (n=5 mice/group) as follows: Control group (gavage, physiological saline, once daily for 3 weeks); low-dose famitinib group (gavage, 50 mg/kg, once daily for 3 weeks); and high-dose famitinib group (gavage, 100 mg/kg, once for 3 weeks). A dose of 50 mg/kg was used for the following experiments. To compare famitinib with other drugs, animals were randomized (n=5 mice/group) as follows: Control group (gavage, physiological saline, once daily for 3 weeks); famitinib group (gavage, 50 mg/kg, once daily for 3 weeks); 5-FU group [10 mg/kg, intraperitoneal (ip), once every 2 days for 3 weeks]; DDP group (3 mg/kg, ip, once weekly for 3 weeks); and PTX group (10 mg/kg, ip, once a week for 3 weeks). Then, tumors and weight were quantified[2]. |
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| References | ||
| Additional Infomation |
Famitinib has been used in trials studying the treatment of Colorectal Cancer, Renal Cell Cancer, Colorectal Cancer Recurrent, Colorectal Cancer Metastatic, and Metastatic Renal Cell Cancer, among others.
Famitinib is an orally bioavailable receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Famitinib binds to and inhibits several RTKs, dysregulated in a variety of tumors, including stem cell factor receptor (c-Kit; SCFR), vascular endothelial growth factor receptor (VEGFR) 2 and 3, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinases Flt1 and Flt3. Inhibition of these RTKs may result in an inhibition of tumor growth and angiogenesis, and eventually tumor regression in tumor cells overexpressing these RTKs. |
| Molecular Formula |
C23H27FN4O2
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|---|---|
| Molecular Weight |
410.48
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| Exact Mass |
410.211
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| Elemental Analysis |
C, 67.30; H, 6.63; F, 4.63; N, 13.65; O, 7.80
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| CAS # |
1044040-56-3
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| Related CAS # |
Famitinib malate;1256377-67-9
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| PubChem CID |
16662431
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| Appearance |
Typically exists as Yellow to orange solids at room temperature
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
677.1±55.0 °C at 760 mmHg
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| Flash Point |
363.3±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.628
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| LogP |
2.61
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
695
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(=O)N(CCN(CC)CC)CCC2NC(/C=C3/C4=C(NC/3=O)C=CC(F)=C4)=C(C)C1=2
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| InChi Key |
GKEYKDOLBLYGRB-LGMDPLHJSA-N
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| InChi Code |
InChI=1S/C23H27FN4O2/c1-4-27(5-2)10-11-28-9-8-19-21(23(28)30)14(3)20(25-19)13-17-16-12-15(24)6-7-18(16)26-22(17)29/h6-7,12-13,25H,4-5,8-11H2,1-3H3,(H,26,29)/b17-13-
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| Chemical Name |
(Z)-5-(2-(diethylamino)ethyl)-2-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one
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| Synonyms |
SHR-1020; Famitinib; SHR1020; SHR-1020; SHR1020; 945380-27-8; CHEMBL1278146; 768FW21J3L; 5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one; SHR 1020.
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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 : ~4.17 mg/mL (~10.16 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 | 2.4362 mL | 12.1809 mL | 24.3617 mL | |
| 5 mM | 0.4872 mL | 2.4362 mL | 4.8723 mL | |
| 10 mM | 0.2436 mL | 1.2181 mL | 2.4362 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.
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