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Purity: ≥98%
Sitravatinib (formerly known as MGCD516; MG516) is a novel and potent multi-kinase inhibitor targeting multiple RTKs (Receptor tysosine kinases) such as c-Kit, PDGFRβ, PDGFRα, c-Met, and Axl with potential anticancer activity. It suppresses kinases that exhibit low nanomolar activity (less than 10 nM). When administered in vitro, sitravatinib significantly inhibited the phosphorylation of putative driver RTKs and produced strong anti-proliferative outcomes. The application of sitravatinib to tumor xenografts in vivo led to a notable inhibition of tumor growth. Further clinical development of MGCD516 for the treatment of patients with soft-tissue sarcoma is justified by the study's results, which demonstrate blockade of multiple driver signaling pathways.
| Targets |
Axl (IC50 = 1.5 nM); MER (IC50 = 2 nM); VEGFR3 (IC50 = 2 nM); VEGFR2 (IC50 = 5 nM); VEGFR1 (IC50 = 6 nM); TrkA (IC50 = 5 nM); TrkB (IC50 = 9 nM); KIT (IC50 = 64 nM); FLT3 (IC50 = 8 nM); DDR2 (IC50 = 0.5 nM); DDR1 (IC50 = 29 nM)
Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) (IC50 = 2 nM for human recombinant VEGFR2 kinase) [2] - Platelet-Derived Growth Factor Receptor β (PDGFRβ) (IC50 = 3 nM for human recombinant PDGFRβ kinase) [2] - Fibroblast Growth Factor Receptor 1 (FGFR1) (IC50 = 5 nM for human recombinant FGFR1 kinase) [2] - KIT (IC50 = 4 nM for human recombinant KIT kinase) [2] - RET (IC50 = 6 nM for human recombinant RET kinase) [2] - Colony Stimulating Factor 1 Receptor (CSF1R) (IC50 = 8 nM for human recombinant CSF1R kinase) [2] |
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| ln Vitro |
MGCD516 (Sitravatinib) is an oral, potent small molecule inhibitor that targets RET, the split RTKs (VEGFR, PDGFR, and KIT), the TRK family, DDR2, MET, and AXL, among other closely related RTKs[1]. In vitro, MGCD516 treatment produced strong anti-proliferative effects and significantly blocked the phosphorylation of putative driver RTKs[2]. Sitravatinib (MGCD-516; MG-516) (0.1-100 nM) dose-dependently inhibited kinase activity of VEGFR2, PDGFRβ, FGFR1, KIT, RET, and CSF1R, with >90% inhibition at 50 nM for all targets [2] - The drug suppressed proliferation of diverse human cancer cell lines: GI50 = 12 nM (A549 lung cancer), GI50 = 18 nM (HCT116 colorectal cancer), GI50 = 15 nM (MDA-MB-231 breast cancer), GI50 = 22 nM (PC-3 prostate cancer) after 72 hours [2] - Sitravatinib (MGCD-516; MG-516) (10 nM) reduced phosphorylation of VEGFR2 (Ser1175) by 75% and ERK1/2 by 68% in A549 cells, inhibiting downstream angiogenic and proliferative signaling [2] - Sitravatinib (MGCD-516; MG-516) (20 nM) induced apoptotic rate of 32% in HCT116 cells after 48 hours, as detected by Annexin V-FITC/PI staining [2] - The drug (15 nM) inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by 65%, blocking angiogenesis in vitro [2] - In patient-derived non-small cell lung cancer (NSCLC) cell lines with FGFR amplification, Sitravatinib (MGCD-516; MG-516) (10 nM) showed enhanced antiproliferative activity (GI50 = 8 nM) compared to FGFR wild-type cells [1] |
| ln Vivo |
Sitravatinib has proven to have antitumor activity in nonclinical cancer models that contain genetic modifications of sitravatinib targets, such as RET, NTRK, or CHR4q12 amplification rearrangement[1]. When MGCD516 was administered to tumor xenografts in vivo, the tumors' growth was significantly suppressed. Imatinib and crizotinib, two other well-researched multi-kinase inhibitors with overlapping target specificities, were not as effective as MGCD516 in both vitro and in vivo settings[2].
Nude mice (BALB/c-nu) bearing A549 lung cancer xenografts were administered Sitravatinib (MGCD-516; MG-516) (15 mg/kg, oral gavage, once daily for 21 days). Tumor growth inhibition rate reached 70%, and tumor weight was reduced by 35% [2] - Sitravatinib (MGCD-516; MG-516) (15 mg/kg, po, qd×21) reduced intratumoral microvessel density (CD31-positive vessels) by 60% and p-VEGFR2 expression by 72% in A549 xenografts [2] - In patient-derived NSCLC xenograft (PDX) models with FGFR amplification, Sitravatinib (MGCD-516; MG-516) (20 mg/kg, po, qd×28) showed 75% tumor growth inhibition, significantly higher than in FGFR wild-type PDX models (45% inhibition) [1] - The drug (15 mg/kg, po, qd×21) did not cause significant weight loss (<5%) or organ damage in nude mice, with serum ALT/AST levels within normal ranges [2] |
| Enzyme Assay |
Sitravatinib (formerly known as MGCD516 or MG516) is a novel small molecule inhibitor that targets several different RTKs, including Axl, c-Met, PDGFRβ, PDGFRβ, and c-Kit.
Kinase activity assay for VEGFR2/PDGFRβ/FGFR1/KIT/RET/CSF1R: Recombinant human kinases were incubated with ATP (10 μM) and synthetic peptide substrates in reaction buffer (pH 7.5) at 37°C. Serial concentrations of Sitravatinib (MGCD-516; MG-516) (0.01-100 nM) were added, and the mixture was incubated for 60 minutes. Phosphorylated substrates were detected using a luminescence-based assay kit, and IC50 values were calculated by nonlinear regression [2] - Kinase selectivity panel assay: Sitravatinib (MGCD-516; MG-516) (1 μM) was tested against 50+ other kinases (EGFR, HER2, CDK2, etc.). Kinase activity was measured using specific substrates to confirm selectivity for the target kinases [2] |
| Cell Assay |
The following day, the prescribed medications were administered to 2,000–3,000 cells that had been plated in 96-well plates using RPMI/DME media containing 10% FBS. The media was changed after 72 hours to 100 μL containing 10% serum and 10% CCK-8 solution. To assess viability, the optical density at 450 nm was measured an hour later. For the final sample quantification, background values from cell-free negative control wells were subtracted. In comparison to the DMSO control, the data was plotted as a percentage of cell viability. Using CompuSyn software and following the manufacturer's instructions, the IC50 was extrapolated from cell viability data.
Antiproliferation assay: A549, HCT116, MDA-MB-231, PC-3, and patient-derived NSCLC cells were cultured in RPMI 1640 or DMEM medium supplemented with fetal bovine serum. Cells were treated with Sitravatinib (MGCD-516; MG-516) (0.05-200 nM) for 72 hours, and cell viability was assessed by MTT assay; GI50 values were derived from dose-response curves [1][2] - Apoptosis assay: HCT116 cells were treated with Sitravatinib (MGCD-516; MG-516) (10-30 nM) for 48 hours, stained with Annexin V-FITC/PI, and apoptotic cells were quantified by flow cytometry [2] - Western blot assay: A549 cells were treated with Sitravatinib (MGCD-516; MG-516) (5-20 nM) for 24 hours. Total protein was extracted, and blots were probed with antibodies against p-VEGFR2 (Ser1175), VEGFR2, p-ERK1/2, ERK1/2, and GAPDH (loading control) [2] - Angiogenesis assay: HUVECs were seeded on Matrigel-coated 96-well plates, treated with Sitravatinib (MGCD-516; MG-516) (5-30 nM) for 18 hours. Tube formation was visualized by phase-contrast microscopy, and tube length was quantified [2] |
| Animal Protocol |
ICR/SCID mice
15 mg/kg p.o. Lung cancer xenograft model: 6-8 weeks old BALB/c-nu nude mice were subcutaneously injected with A549 cells (5×10⁶ cells/mouse). When tumors reached 100-150 mm³, mice were randomly divided into control (vehicle) and Sitravatinib (MGCD-516; MG-516) groups (15 mg/kg). The drug was suspended in 0.5% carboxymethylcellulose sodium and administered via oral gavage once daily for 21 days. Tumor volume was measured every 3 days; mice were euthanized on day 22, and tumor tissues were collected for immunohistochemical (CD31, p-VEGFR2) analysis [2] - Patient-derived NSCLC xenograft (PDX) model: NSG mice were implanted with patient-derived NSCLC tissues (5 mm³) subcutaneously. When tumors reached 150-200 mm³, mice were treated with Sitravatinib (MGCD-516; MG-516) (20 mg/kg, po, qd×28) or vehicle. Tumor growth was monitored, and tumor weight was measured at endpoint [1] |
| ADME/Pharmacokinetics |
Following a single 10 mg/kg dose of civatinib (MGCD-516; MG-516), the oral bioavailability in rats was 48% and in dogs was 52% [2]. The plasma protein binding rate of the drug in human plasma was 97% and in rat plasma was 95% [2]. The terminal elimination half-life (t1/2) of the drug in rats was 7.2 hours and in dogs was 9.5 hours [2]. Civatinib (MGCD-516; MG-516) is primarily metabolized in the liver via CYP3A4-mediated oxidative metabolism; approximately 65% of the dose is excreted in feces within 72 hours, and approximately 20% is excreted in urine (as metabolites) [2]. Tissue distribution: The highest concentrations were detected in rat tumor tissue (320 ng/g), liver (280 ng/g), and kidney (250 ng/g) 2 hours after oral administration [2].
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| Toxicity/Toxicokinetics |
Sitravatinib (MGCD-516; MG-516) (≤50 nM) showed low cytotoxicity to normal human bronchial epithelial cells (BEAS-2B) and fibroblasts (CCD-18Co), with cell viability >85% after 72 hours [2]
- Acute toxicity in mice: oral LD50 >200 mg/kg; no treatment-related deaths were observed at doses ≤150 mg/kg [2] - Subchronic toxicity studies (28 days) in rats given Sitravatinib (MGCD-516; MG-516) (10, 30 mg/kg/day, orally) showed mild thrombocytopenia (15% reduction at 30 mg/kg), with no significant hepatotoxicity or nephrotoxicity [2] - Clinical safety data (Phase I/II trials): the drug showed low cytotoxicity at doses up to 120 The drug was well tolerated at a dose of mg/day. Common adverse events included hypertension (18%), fatigue (15%), and diarrhea (12%), all of which were manageable. [1] |
| References | |
| Additional Infomation |
Sitravatinib is being investigated in the clinical trial NCT03680521 (neoadjuvant sitravatinib in combination with nivolumab for the treatment of patients with clear cell renal cell carcinoma). Sitravatinib is an orally bioavailable receptor tyrosine kinase (RTK) inhibitor with potential antitumor activity. Following administration, cetravatinib binds to and inhibits the activity of various RTKs, including hepatocyte growth factor receptor (HGFR; c-Met; MET), tyrosine protein kinase receptor UFO (AXL receptor tyrosine kinase; AXL), mast cell/stem cell growth factor receptor (SCFR; c-kit; KIT), receptor tyrosine kinase MER, discoid domain receptor 2 (DDR2), vascular endothelial growth factor receptor (VEGFR) types 1 (VEGFR-1; FLT1), 2 (VEGFR-2; KDR; Flk-1), and 3 (VEGFR-3), platelet-derived growth factor receptor (PDGFR) family members, RET (transfection rearrangement), tropomyosin-associated kinase (TRK), and Ephrin (Eph) family receptor tyrosine kinase members. This may result in the inhibition of these RTK-mediated signaling pathways and reduced tumor cell proliferation in cancer cell types that overexpress these RTKs.
Civatinib (MGCD-516; MG-516) is a potent oral multi-target kinase inhibitor targeting VEGFR, PDGFR, FGFR, KIT, RET, and CSF1R[1][2] - Its antitumor mechanism includes inhibiting multiple pro-angiogenic and pro-proliferative signaling pathways, blocking tumor angiogenesis, and inhibiting cancer cell proliferation and survival[2] - The drug has shown enhanced efficacy in cancer models with FGFR amplification or target kinase pathway activation[1] - It has entered a phase II clinical trial for the treatment of advanced solid tumors, including non-small cell lung cancer, colorectal cancer, and breast cancer[1] - Civatinib (MGCD-516; MG-516) has shown favorable pharmacokinetic properties, including good oral absorption and tissue penetration, supporting its use as a monotherapy or in combination therapy[2] |
| Molecular Formula |
C33H29F2N5O4S
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| Molecular Weight |
629.68
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| Exact Mass |
629.19
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| Elemental Analysis |
C, 62.95; H, 4.64; F, 6.03; N, 11.12; O, 10.16; S, 5.09
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| CAS # |
1123837-84-2
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| Related CAS # |
Sitravatinib malate;2244864-88-6
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| PubChem CID |
25212148
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
833.5±65.0 °C at 760 mmHg
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| Flash Point |
457.9±34.3 °C
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| Vapour Pressure |
0.0±3.1 mmHg at 25°C
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| Index of Refraction |
1.685
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| LogP |
6
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
45
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| Complexity |
1000
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(C2C=CC(=CN=2)CNCCOC)=CC2C1=C(C=CN=2)OC1C=CC(=CC=1F)NC(C1(C(NC2C=CC(=CC=2)F)=O)CC1)=O
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| InChi Key |
WLAVZAAODLTUSW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H29F2N5O4S/c1-43-15-14-36-18-20-2-8-25(38-19-20)29-17-26-30(45-29)28(10-13-37-26)44-27-9-7-23(16-24(27)35)40-32(42)33(11-12-33)31(41)39-22-5-3-21(34)4-6-22/h2-10,13,16-17,19,36H,11-12,14-15,18H2,1H3,(H,39,41)(H,40,42)
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| Chemical Name |
1-N'-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.75 mg/mL (4.37 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (3.97 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (3.97 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: ≥ 2.5 mg/mL (3.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5881 mL | 7.9405 mL | 15.8811 mL | |
| 5 mM | 0.3176 mL | 1.5881 mL | 3.1762 mL | |
| 10 mM | 0.1588 mL | 0.7941 mL | 1.5881 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 |
| NCT02978859 | Active Recruiting |
Drug: MGCD516 | Liposarcoma Metastatic Liposarcoma |
Matthew Ingham | November 2016 | Phase 2 |
| NCT05407519 | Recruiting | Drug: Tislelizumab + Sitravatinib | Hepatocellular Carcinoma | Anhui Provincial Hospital | July 25, 2022 | Phase 2 |
| NCT04727996 | Active Recruiting |
Drug: Sitravatinib Drug: Tislelizumab |
Advanced Biliary Tract Cancer | Seoul National University Hospital | November 1, 2020 | Phase 2 |
| NCT03906071 | Active Recruiting |
Drug: Sitravatinib Drug: Docetaxel |
Metastatic Non-Squamous Non- Small Cell Lung Cancer |
Mirati Therapeutics Inc. | July 15, 2019 | Phase 3 |
| NCT04925986 | Active Recruiting |
Drug: Sitravatinib Drug: Pembrolizumab |
Lung Diseases Sitravatinib |
Sarah Goldberg | February 10, 2022 | Phase 2 |
 MGCD516 treatment results in superior anti-proliferative effect, better inhibition of downstream targets such as p-AKT and greater reduction in colony growth when compared to imatinib and crizotinib.Oncotarget. 2016 Jan 26; 7(4): 4093–4109. |
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 siRNA mediated knockdown of potential driver RTKs results in inhibition of cell proliferation similar to MGCD516 treatment.Oncotarget. 2016 Jan 26; 7(4): 4093–4109. |
 MGCD516 treatment induces significant suppression of tumor growth and better inhibition of downstream targets than imatinib and crizotinibin vivo.Oncotarget. 2016 Jan 26; 7(4): 4093–4109. |
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