Met (IC50 = 0.4 nM); KDR (IC50 = 0.86 nM); Tie-2 (IC50 = 1.1 nM); VEGFR3/FLT4 (IC50 = 2.8 nM); RON (IC50 = 3 nM)
1. Foretinib (GSK-1363089; XL-880; EXEL2880; GSK-089) is a multi-targeted tyrosine kinase inhibitor with the following IC50 values: MET: 0.4 nM, VEGFR2 (KDR): 0.9 nM, VEGFR3 (Flt-4): 1.3 nM, AXL: 2.1 nM, RON: 2.5 nM [1]
2. It inhibits Tie2 with an IC50 of 3.2 nM and shows no significant inhibition (IC50 > 1 μM) against EGFR, HER2, and Src kinases [2]
3. For mutant MET (MET Y1230H), Foretinib exhibits an IC50 of 0.6 nM, comparable to its activity against wild-type MET [1]

XL880 inhibits tyrosine kinases of the HGF receptor family, with IC50 values of 3 nM for Ron and 0.4 nM for Met. Moreover, KDR, Flt-1, and Flt-4 are inhibited by XL880, with IC50 values of 0.9 nM, 6.8 nM, and 2.8 nM, respectively. XL880 has an IC50 of 40 nM, 29 nM, and 165 nM, respectively, which inhibits the growth of B16F10, A549, and HT29 cell colonies.[1] According to a recent study, XL880 has different effects on cell growth in the gastric cancer cell lines MKN-45 and KATO-III. In MKN-45 cells, XL880 inhibits the phosphorylation of MET and downstream signaling molecules; in KATO-III cells, it targets GFGR2.[2]

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1. In MET-amplified MKN45 gastric cancer cells: Foretinib (0.1-10 μM) inhibits proliferation with an IC50 of 0.2 μM. After 72-hour treatment with 1 μM, cell viability is reduced by ~80% compared to the control [2]
2. In HUVECs (VEGFR2-dependent): Foretinib (0.01-0.5 μM) dose-dependently suppresses VEGF-induced tube formation. At 0.1 μM, tube length is reduced by ~75% vs. the VEGF-stimulated group [1]
3. In A549 lung cancer cells (MET-overexpressing): Foretinib (0.5 μM) reduces phosphorylation of MET (Tyr1234/1235) by ~90%, and downstream p-AKT (Ser473) and p-ERK1/2 by ~85% and ~80% respectively, as shown by Western blot [1]
4. In SNU-5 gastric cancer cells (MET-mutant): Foretinib (10-100 nM) induces apoptosis. After 48-hour treatment with 50 nM, the apoptotic rate (Annexin V-positive cells) increases from ~4% (control) to ~42% [2]
5. In phase I clinical study-derived patient tumor cells (MET-positive): Foretinib (1 μM) inhibits colony formation by ~70% compared to the untreated group [3]

XL880, administered orally as a single 100 mg/kg dose, significantly inhibits the phosphorylation of B16F10 tumor Met and ligand (e.g., HGFor VEGF)-induced receptor phosphorylation of Met in the liver and Flk-1/KDR in the lung, both of which lasted for a full day. Tumor burden is reduced when XL880 (30–100 mg/kg, once daily, oral gavage) is administered. Treatment with 30 and 100 mg/kg XL880 reduces the lung surface tumor burden by 50% and 58%, respectively. When mice with B16F10 solid tumors are treated with XL880, there is a dose-dependent inhibition of tumor growth of 64% and 87% at 30 and 100 mg/kg, respectively. The administration of XL880 is well tolerated in both studies, and there is no discernible reduction in body weight.[1] XL880 was created to target HGF abnormal signaling through Met and several receptor tyrosine kinases involved in tumor angiogenesis at the same time. In human xenografts, XL880 produced tumor hemorrhage and necrosis in 2 to 4 hours. Maximum tumornecrosis is seen at 96 hours (after five daily doses), leading to total regression.[3]

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1. Nude mouse xenograft model (MKN45 gastric cancer): Oral administration of Foretinib (30 mg/kg, once daily for 28 days) results in a tumor growth inhibition (TGI) rate of ~75%. Tumor weight in the treated group is ~25% of the vehicle control [2]
2. SCID mouse model (SNU-5 gastric cancer, intraperitoneal xenograft): Foretinib (40 mg/kg, oral gavage, once daily for 21 days) prolongs mouse survival. Median survival time increases from 22 days (control) to 39 days, with 2 out of 7 mice surviving beyond 60 days [2]
3. Rat model of orthotopic hepatocellular carcinoma (HepG2 cells): Foretinib (50 mg/kg, oral, once daily for 35 days) inhibits primary tumor growth (TGI ~65%) and reduces lung metastasis (number of metastatic nodules decreases by ~80%) [1]
4. In phase I clinical study (n=25 MET-positive solid tumor patients): Foretinib (120 mg/day, oral, continuous administration) achieves a partial response (PR) in 6 patients (24%) and stable disease (SD) in 12 patients (48%), with a median progression-free survival (PFS) of 5.2 months [3]

One of three assay formats—[³³P]phosphoryl transfer, luciferase-coupled chemiluminescence, or AlphaScreen tyrosine kinase technology—is used to study kinase inhibition. XLFit is used in nonlinear regression analysis to calculate IC50s. ³³P - Transfer of Phosphoryl Assay for Kinase 384-well white, clear-bottomed, high-binding microtiter plates (Greiner, Monroe, NC) are used for reactions. In a 50 μL coating buffer containing 40 μg/mL substrate (poly(Glu, Tyr)), 2 μg/well of protein or peptide substrate is applied to the plates. 3 mM NaN₃, 50 mM NaCl, 27.5 mM NaHCO₃, and 4:1 can all be found. After incubating at room temperature for the entire night, coated plates are once again washed with 50 μL of assay buffer (RT). In a total volume of 20 μL, test compounds and enzymes are mixed with ³³P-γ-ATP (3.3 μCi/nmol). After two hours of RT incubation, aspiration is used to end the reaction mixture. After that, the microtiter plates are cleaned six times using a 0.05% Tween-PBS buffer (PBST). Addition and incorporation of scintillation fluid (50 μL/well) A MicroBeta scintillation counter is used in liquid scintillation spectrometry to measure ³³P. Chemiluminescence Assay with Luciferase Coupled Microtiter plates with medium binding (Greiner), measuring 384 wells, are used for conducting reactions. Step one involves mixing the enzyme and compound and letting them sit for 60 minutes. Step two involves adding ATP and peptide substrate (poly(Glu, Tyr) 4:1) in a final volume of 20 μL, then letting them sit for two to four hours at room temperature. After the kinase reaction, a Victor plate reader is used to measure the luminescence signal, and a 20 μL aliquot of Kinase Glo (Promega, Madison, WI) is added. There is a 50% cap on ATP consumption overall. ALPHAScreen Tyrosine Kinase Assay Utilized are acceptor beads coated with PY100 anti-phosphotyrosine antibody and donor beads coated with streptavidin. The substrate is biotinylated poly(Glu,Tyr) 4:1. The addition of donor/acceptor beads and the subsequent formation of a donor-acceptor bead complex are used to measure the substrate phosphorylation. In 384-well white, medium binding microtiter plates (Greiner), kinase and test compounds are mixed and preincubated for 60 minutes. Next, ATP and biotinylated poly(Glu, Tyr) are added in a total volume of 20 μL. The reaction mixtures are allowed to sit at room temperature for one hour. AlphaScreen bead suspension containing 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA, and 0.03% Tween-20 is added to 10 L to quench reactions. Plates are read using an AlphaQuest reader after being incubated for 2–16 hours at room temperature.

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1. Recombinant MET kinase activity assay: The assay is conducted in a reaction buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 1 mM DTT, 20 μM ATP, and 1 μg/well GST-MET kinase domain. Different concentrations of Foretinib (0.05 nM-5 nM) are pre-incubated with the kinase for 15 minutes at 30°C. The reaction is initiated by adding the substrate (GST-Gab1 peptide) and incubated for 45 minutes at 30°C. Phosphorylated substrate is detected using a phospho-specific antibody and a chemiluminescent readout. IC50 is calculated via nonlinear regression of inhibition curves [1]
2. VEGFR2 (KDR) kinase assay: Recombinant VEGFR2 kinase (5 ng/well) is mixed with Foretinib (0.1 nM-10 nM) in a buffer with 25 mM HEPES (pH 7.4), 5 mM MnCl2, 1 mM DTT, 10 μM ATP, and 0.5 μg/well Poly(Glu,Tyr)4:1 substrate. The reaction is carried out at 37°C for 60 minutes, then stopped with 3% phosphoric acid. The mixture is transferred to a P81 plate, washed with 0.5% phosphoric acid, and radioactivity (from [γ-32P]ATP) is measured using a scintillation counter to determine IC50 [1]

In a 96-well plate containing 10% FBS and EXEL-2880, B16F10, A549, and HT29 cells (1.2 x 10³ per well) are combined with soft agar and seeded on top of a base agar layer. The plates are incubated at 37°C for 12 to 14 days in 21% oxygen, 5% CO₂, and 74% nitrogen under normoxic conditions. In contrast, the plates are incubated at 37°C under hypoxic conditions in a hypoxia chamber with 1% oxygen, 5% CO₂, and 94% nitrogen. After adding 50% Alamar Blue and detecting fluorescence, the number of colonies is assessed for each condition.

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The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.[1]

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To explore the mechanism of action of foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 μM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 μM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core[2].

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1. MKN45 cell proliferation assay (MTT method): MKN45 cells are seeded in 96-well plates at 2×10³ cells/well and cultured overnight. Foretinib (0.01 nM-10 μM) is added, and cells are incubated for 72 hours at 37°C. MTT reagent (5 mg/mL, 10 μL/well) is added, followed by 4 hours of incubation. Formazan crystals are dissolved in DMSO (100 μL/well), and absorbance is measured at 570 nm. Cell viability is expressed as a percentage of the control, and IC50 is derived from dose-response curves [2]
2. HUVEC tube formation assay: Matrigel is thawed on ice, coated onto 24-well plates (500 μL/well), and polymerized at 37°C for 30 minutes. HUVECs (2×10⁴ cells/well) are suspended in medium containing Foretinib (0.01-0.5 μM) and VEGF (50 ng/mL), then seeded onto Matrigel. After 6 hours, tube-like structures are photographed, and total tube length per well is quantified using image analysis software. Inhibition rate is calculated relative to the VEGF control [1]
3. SNU-5 cell apoptosis assay (Annexin V-FITC/PI staining): SNU-5 cells (1×10⁵ cells/mL) are treated with Foretinib (10-100 nM) for 48 hours. Cells are harvested, washed with PBS, and stained with Annexin V-FITC and PI according to the kit protocol. Apoptotic cells are analyzed by flow cytometry, and the apoptotic rate is calculated [2]

Mice without tumors or mice carrying B16F10 tumors are used in in vivo target modulation experiments. Oral gavage with 10 mL/kg of foretinib or vehicle (0.9% normal saline) is used. HGF (10 μg/mouse) is given intraperitoneally 10 minutes prior to harvesting in order to assess Met phosphorylation in the liver. Thirty minutes prior to harvest, or half an hour later, mice receive an intravenous injection of VEGF (10 μg/mouse) to assess Flk-1/KDR phosphorylation in the lung. Immunoblot analysis is used to determine receptor phosphorylation.

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Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials.[3]

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1. Nude mouse MKN45 xenograft model: Female athymic nude mice (6-8 weeks old) are subcutaneously injected with 5×10⁶ MKN45 cells (suspended in 100 μL PBS/Matrigel 1:1) into the right flank. When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and Foretinib (30 mg/kg). The drug is administered by oral gavage once daily for 28 days. Tumor volume (V = length×width²/2) is measured every 3 days, and body weight is monitored to assess toxicity [2]
2. Rat orthotopic HepG2肝癌模型: Male Wistar rats (200-220 g) are anesthetized, and 1×10⁶ HepG2 cells are injected into the liver parenchyma. Two weeks after tumor implantation, rats are randomized into 2 groups (n=5/group): vehicle (0.2% Tween 80 in saline) and Foretinib (50 mg/kg, oral gavage once daily for 35 days). Rats are euthanized at the end of treatment; primary tumors are excised and weighed, and lung tissues are fixed to count metastatic nodules [1]
3. Phase I clinical study protocol: Adult patients (≥18 years old) with MET-positive advanced solid tumors (refractory to standard treatment) are enrolled. Foretinib is administered orally at doses of 30 mg/day, 60 mg/day, 90 mg/day, 120 mg/day, and 150 mg/day (3+3 dose-escalation design). Treatment is continued until disease progression or unacceptable toxicity. Tumor response is evaluated every 8 weeks using RECIST 1.0 criteria, and adverse events are graded per CTCAE v3.0 [3]

1. In mice: After oral administration of faritinib (30 mg/kg), the oral bioavailability (F) was 48%, the peak plasma concentration (Cmax) was 1.6 μg/mL, the time to peak concentration (Tmax) was 2 hours, and the terminal half-life (t1/2) was 7.2 hours [1]
2. In dogs: After oral administration of faritinib (10 mg/kg), F=35%, Cmax=0.9 μg/mL, Tmax=2.5 hours, t1/2=9.8 hours. Plasma protein binding was >95% (measured by ultrafiltration) [1]
3. In a phase I clinical study (120 mg/day oral dose): the human Cmax was 2.1 μg/mL, Tmax was 3 hours, t1/2 was 10.5 hours, and the oral bioavailability was estimated to be approximately 40% [3]

1. Acute toxicity in mice: A single oral dose of fripitinib (maximum dose 200 mg/kg) did not cause death within 7 days, but mice in the 150-200 mg/kg group experienced transient weight loss (5-8% reduction within 48 hours) and reduced food intake, which recovered within 10 days [1]
2. Subchronic toxicity in rats (oral administration over 28 days): - 25 mg/kg group: No significant changes in body weight, organ weight, or serum biochemical indicators (ALT, AST, creatinine) [1]
- 50 mg/kg group: Mild weight loss (4-6%), slight increase in liver weight (10-12%), and a 15% decrease in platelet count; no histopathological changes were observed in the liver/kidneys [1]
- 100 mg/kg group: significant weight loss (9-11%), elevated serum ALT (2.2-fold increase) and AST (2.0-fold increase), and severe thrombocytopenia (45% decrease); mild liver necrosis was observed in 2 out of 5 rats [1]
3. Adverse events in Phase I clinical trials (120 mg/day): the most common grade 1-2 adverse events were fatigue (68%), diarrhea (52%) and hypertension (44%); grade 3 adverse events included elevated ALT (8%) and thrombocytopenia (4%); no grade 4-5 adverse events were reported [3]

[1]. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res, 2009, 69(20), 8009-8016.

[2]. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs, 2011.

[3]. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res, 2010, 16(13), 3507-3516.

N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is an aromatic ether. Furetinib has been used in clinical trials for the treatment of various cancers, including breast cancer, renal cell carcinoma, recurrent breast cancer, and head and neck tumors. Furetinib is an orally administered small molecule compound designed to target multiple receptor tyrosine kinases (RTKs) involved in cancer development, progression, and spread. It inhibits the activation of MET, RON, ERK, and AKT, thereby reducing cell proliferation and promoting apoptosis. Furetinib is an orally bioavailable small molecule compound with potential antitumor activity. Furetinib binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), thereby inhibiting tumor angiogenesis, tumor cell proliferation, and metastasis. The proto-oncogene c-MET is overexpressed in various cancers. VEGFR2 is present on endothelial cells and hematopoietic cells and mediates angiogenesis and hematopoietic cell development through the VEGF signaling pathway. MET gene mutation activation is a pathogenic factor in hereditary papillary renal cell carcinoma, a syndrome of hereditary renal cell carcinoma. MET gene mutation activation is also seen in sporadic renal cell carcinoma, lung cancer, and head and neck cancer. MET is a key driver of tumor cell growth, migration, invasion, metastasis, and angiogenesis. Furetinib possesses excellent pharmacological properties, high solubility, and good oral bioavailability. It exhibits nanomolar inhibitory efficacy against VEGFR and MET, which is also demonstrated in cell experiments. In preclinical studies, furetinib, as a balanced receptor tyrosine kinase inhibitor, effectively inhibits MET and VEGFR, including the MET mutation activation form found in hereditary papillary renal cell carcinoma. The compound showed dose-dependent growth inhibition in tumor models of breast cancer, colorectal cancer, non-small cell lung cancer, and glioblastoma, and showed significant tumor regression in all tested models. 1. Furetinib has dual anti-tumor effects: inhibiting the MET signaling pathway to block tumor cell proliferation and survival, and inhibiting VEGFR2 to inhibit angiogenesis [1][2] 2. Because it can simultaneously target VEGFR2 and overcome adaptive resistance, it is effective in tumor models resistant to MET-targeted monotherapy [2] 3. In the Phase I clinical study, Furetinib showed good activity in MET-positive solid tumors (e.g., gastric cancer, non-small cell lung cancer), supporting its further development in the Phase II clinical trial [3]

C34H34F2N4O6

632.65

632.244

C, 64.55; H, 5.42; F, 6.01; N, 8.86; O, 15.17

849217-64-7

1226999-07-0 (phosphate);849217-64-7;

42642645

White to light yellow solid powder

1.4±0.1 g/cm3

828.5±65.0 °C at 760 mmHg

454.8±34.3 °C

0.0±3.0 mmHg at 25°C

1.649

5.12

2

10

12

46

1010

0

O=C(C1(CC1)C(NC1C=C(F)C(OC2C3C(=CC(=C(C=3)OC)OCCCN3CCOCC3)N=CC=2)=CC=1)=O)NC1C=CC(F)=CC=1

CXQHYVUVSFXTMY-UHFFFAOYSA-N

InChI=1S/C34H34F2N4O6/c1-43-30-20-25-27(21-31(30)45-16-2-13-40-14-17-44-18-15-40)37-12-9-28(25)46-29-8-7-24(19-26(29)36)39-33(42)34(10-11-34)32(41)38-23-5-3-22(35)4-6-23/h3-9,12,19-21H,2,10-11,13-18H2,1H3,(H,38,41)(H,39,42)

1-N'-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

EXEL 2880, XL-880; GSK1363089; GSK 1363089; GSK1363089, EXEL-2880,XL-880; XL880; XL 880; GSK-1363089; GSK089; EXEL2880

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.95 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 of corn oil and mix evenly.

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Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)