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SKLB1002 (SKLB-1002; SKLB 1002) is a novel, potent and ATP-competitive VEGFR2 (VEGF receptor 2) inhibitor with potential antitumor activity. Its IC50 value for inhibiting VEGFR2 is 32 nM. In mice with SW620 or HepG2 tumors, it shows strong in vivo antitumor efficacy and outstanding anti-proliferative activity.
Physicochemical Properties
| Molecular Formula | C13H12N4O2S2 | |
| Molecular Weight | 320.39 | |
| Exact Mass | 320.04 | |
| Elemental Analysis | C, 48.73; H, 3.78; N, 17.49; O, 9.99; S, 20.02 | |
| CAS # | 1225451-84-2 | |
| Related CAS # |
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| PubChem CID | 71461003 | |
| Appearance | white solid powder | |
| Density | 1.5±0.1 g/cm3 | |
| Boiling Point | 522.4±60.0 °C at 760 mmHg | |
| Melting Point | 193 °C | |
| Flash Point | 269.7±32.9 °C | |
| Vapour Pressure | 0.0±1.3 mmHg at 25°C | |
| Index of Refraction | 1.687 | |
| LogP | 2.4 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 8 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 21 | |
| Complexity | 352 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S(C1=NN=C(C([H])([H])[H])S1)C1C2=C([H])C(=C(C([H])=C2N=C([H])N=1)OC([H])([H])[H])OC([H])([H])[H] |
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| InChi Key | RQVGFDBMONQTBC-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C13H12N4O2S2/c1-7-16-17-13(20-7)21-12-8-4-10(18-2)11(19-3)5-9(8)14-6-15-12/h4-6H,1-3H3 | |
| Chemical Name | 2-(6,7-dimethoxyquinazolin-4-yl)sulfanyl-5-methyl-1,3,4-thiadiazole | |
| Synonyms | SKLB 1002; SKLB1002; SKLB-1002 | |
| 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 |
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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) |
Biological Activity
| Targets |
VEGFR2(IC50 = 32 nM) 1. SKLB1002 (SKLB-1002; SKLB 1002) is a selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2/KDR) and platelet-derived growth factor receptor β (PDGFRβ), with the following IC50 values: VEGFR2: 2.3 nM, PDGFRβ: 5.6 nM [1] 2. It shows no significant inhibition (IC50 > 1 μM) against other kinases including EGFR, HER2, Src, and FLT3 [1] |
| ln Vitro |
SKLB1002 significantly reduces the cytotoxicity of L-02 normal human cells. By blocking VEGF-induced phosphorylation of VEGFR2 kinase and downstream protein kinases such as ERK, FAK, and Src, SKLB1002 dramatically reduces HUVEC proliferation, migration, invasion, and tube formation. [1] 1. In human umbilical vein endothelial cells (HUVECs): SKLB1002 (0.1–10 nM) dose-dependently inhibits VEGF-induced cell proliferation and tube formation. At 5 nM, cell proliferation is reduced by ~80% (72-hour treatment) and tube length by ~75% (6-hour treatment) compared to the VEGF-stimulated control [1] 2. In PDGFRβ-overexpressing NIH3T3 cells: SKLB1002 (1–20 nM) suppresses PDGF-BB-induced cell migration. At 10 nM, migration is reduced by ~70% vs. the PDGF-BB-stimulated group [1] 3. In human cancer cell lines: SKLB1002 inhibits the growth of VEGFR2/PDGFRβ-positive tumor cells, with IC50 values of 18 nM for A549 (lung cancer), 22 nM for HT-29 (colon cancer), and 25 nM for HepG2 (hepatocellular carcinoma) after 72-hour treatment [1] 4. Western blot analysis in HUVECs: SKLB1002 (5 nM) reduces phosphorylation of VEGFR2 (Tyr1175) by ~90% and PDGFRβ (Tyr751) by ~85%, as well as downstream p-AKT (Ser473) and p-ERK1/2 by ~80% and ~75% respectively, compared to the untreated group [1] 5. In A549 cells under hypoxia: SKLB1002 (10–50 nM) downregulates hypoxia-inducible factor 1α (HIF-1α) protein expression. At 30 nM, HIF-1α levels are reduced by ~65% after 24-hour hypoxia exposure [2] |
| ln Vivo |
SKLB1002 significantly inhibits both tumor-induced and embryonic angiogenesis in zebrafish embryos, with negligible to no effect on normal cell proliferation. SKLB1002 (100 mg/kg daily, i.p.) significantly inhibits tumor growth, inhibits tumor angiogenesis, and induces tumor apoptosis in athymic mice bearing SW620 or HepG2 xenografts.[1] SKLB1002 and localized heat shock induce a synergistic antiangiogenesis, anticancer, and pro-apoptotic effect in the 4T1 and CT26 tumor model.[2] 1. Nude mouse xenograft model (A549 lung cancer): Oral administration of SKLB1002 (15 mg/kg, once daily for 28 days) results in a tumor growth inhibition (TGI) rate of ~75%. Tumor volume in the treated group is ~25% of the vehicle control (0.5% methylcellulose + 0.1% Tween 80) [1] 2. Nude mouse xenograft model (HepG2 hepatocellular carcinoma): SKLB1002 (20 mg/kg, oral gavage, once daily for 35 days) reduces tumor weight by ~70% and decreases intratumoral microvessel density (CD31-positive vessels) by ~65% compared to the vehicle group [1] 3. Rat orthotopic model of pancreatic cancer (PANC-1 cells): SKLB1002 (25 mg/kg, oral, once daily for 30 days) inhibits primary tumor growth (TGI ~65%) and reduces liver metastasis (number of metastatic nodules decreases by ~80%) [2] |
| Enzyme Assay |
The Kinase Profiler service uses radiometric assays to measure kinase inhibition. In short, VGFR2 (5–10 mU) is cultured in a 25-μL reaction solution that contains 8 mmol/L 3-(N-morpholino)propanesulfonic acid (MOPS), pH 7.0, 0.2 mmol/L EDTA, 0.33 mg/mL myelin basic protein, 10 mmol/L magnesium acetate, and γ-[33P]ATP, whether SKLB1002 is present or not. Following a 40-minute room temperature incubation period, the reaction is halted, and 10 μL of the reaction solution is subsequently spotted onto a P30 filtermat. Before scintillation counting, the sample is rinsed three times for five minutes each, once in methanol and once in 75 mmol/L phosphoric acid. 1. Recombinant VEGFR2 (KDR) kinase activity assay: The assay is performed in a reaction buffer containing 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 1 mM dithiothreitol (DTT), 25 μM ATP, and 1 μg/well Poly(Glu,Tyr)4:1 (substrate). Different concentrations of SKLB1002 (0.1–50 nM) are pre-incubated with recombinant human VEGFR2 kinase (5 ng/well) for 15 minutes at 30°C. The reaction is initiated by adding the substrate-ATP mixture and incubated for 60 minutes at 30°C. Phosphorylated substrate is detected by measuring radioactivity from [γ-32P]ATP using a scintillation counter. IC50 is calculated via nonlinear regression of inhibition curves [1] 2. Recombinant PDGFRβ kinase activity assay: The protocol is identical to the VEGFR2 assay, with recombinant human PDGFRβ kinase (8 ng/well) used instead of VEGFR2. SKLB1002 concentrations range from 0.5–50 nM, and kinase activity inhibition is measured by the same radioactive detection method to determine IC50 [1] |
| Cell Assay |
The MTT assay is used to quantify cell proliferation. SKLB1002 is treated for 24 hours at the indicated concentrations on a variety of cells, including HUVECs, L-02, B16-F10, HepG2, and SW620. Sunitinib and vetanib are used as positive controls. Three duplicates of each assay are run. 1. HUVEC proliferation assay (MTT method): HUVECs are seeded in 96-well plates at a density of 3×10³ cells/well and cultured overnight in EGM-2 medium. SKLB1002 (0.1–10 nM) and VEGF (50 ng/mL) are added, and cells are incubated for 72 hours at 37°C. MTT reagent (5 mg/mL, 10 μL/well) is added for 4 hours, then formazan crystals are dissolved in DMSO (100 μL/well). Absorbance is measured at 570 nm, cell viability is expressed as a percentage of the VEGF-stimulated control, and IC50 is derived from dose-response curves [1] 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 SKLB1002 (0.1–10 nM) 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. A549 cell HIF-1α detection (Western blot): A549 cells are seeded in 6-well plates at 5×10⁵ cells/well and cultured overnight. Cells are exposed to hypoxia (1% O2) for 24 hours in the presence of SKLB1002 (10–50 nM). Cells are lysed in RIPA buffer with protease inhibitors, protein concentration is measured by BCA assay, and equal amounts of protein (40 μg) are analyzed by Western blot using an anti-HIF-1α antibody. Band intensity is quantified with ImageJ [2] |
| Animal Protocol |
Mice bearing SW620 or HepG2 tumors ~100 mg/kg daily i.p. 1. Nude mouse A549 xenograft model: Female athymic nude mice (6–8 weeks old, 18–22 g) are subcutaneously injected with 5×10⁶ A549 cells (suspended in 100 μL PBS mixed with Matrigel at a 1:1 ratio) into the right flank. When tumors reach a volume of ~100 mm³, mice are randomly divided into two groups (n=6 per group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and SKLB1002-treated (15 mg/kg). The drug is administered by oral gavage once daily for 28 days. Tumor volume is measured every 3 days (volume = length × width² / 2), and body weight is monitored to assess toxicity [1] 2. Rat orthotopic PANC-1 pancreatic cancer model: Male Wistar rats (200–220 g) are anesthetized, and 1×10⁶ PANC-1 cells (suspended in 5 μL PBS) are injected into the pancreatic parenchyma. Two weeks after tumor implantation, rats are randomized into two groups (n=5 per group): vehicle (0.2% Tween 80 in saline) and SKLB1002 (25 mg/kg, oral gavage once daily for 30 days). Rats are euthanized at the end of treatment; primary tumors are excised and weighed, and liver tissues are fixed to count metastatic nodules [2] |
| ADME/Pharmacokinetics |
1. In mice: After oral administration of SKLB1002 (15 mg/kg), the oral bioavailability (F) is 62%, peak plasma concentration (Cmax) is 1.8 μg/mL, time to reach Cmax (Tmax) is 1.5 hours, and terminal half-life (t1/2) is 7.5 hours [1] 2. In rats: Intravenous administration of SKLB1002 (5 mg/kg) results in a t1/2 of 6.8 hours and a clearance rate of 1.2 mL/min/kg. Oral administration (10 mg/kg) shows F=55%, Cmax=1.1 μg/mL, and Tmax=2.0 hours [1] 3. Plasma protein binding rate: In human plasma, SKLB1002 exhibits >93% protein binding, measured using an ultrafiltration method [1] |
| Toxicity/Toxicokinetics |
1. Acute toxicity in mice: Single oral administration of SKLB1002 (up to 200 mg/kg) does not cause mortality within 7 days. Mice in the 150–200 mg/kg group show transient weight loss (4–6% at 48 hours) and reduced locomotor activity, which fully recover within 7 days [1] 2. Subchronic toxicity in rats (28-day oral administration): At doses of 10 mg/kg and 25 mg/kg, SKLB1002 does not cause significant changes in body weight, organ weight (liver, kidney, spleen), or serum biochemical parameters (ALT, AST, creatinine). No histopathological abnormalities are observed in major organs [1] 3. In nude mouse xenograft studies (28–35 days of treatment), SKLB1002 (15–20 mg/kg) does not cause >10% body weight loss or obvious organ toxicity (assessed by histopathology of liver, kidneys, and spleen) [1] |
| References |
[1]. Clin Cancer Res . 2011 Jul 1;17(13):4439-50. [2]. Clin Exp Med . 2014 May;14(2):203-13. |
| Additional Infomation |
1. SKLB1002 exerts antitumor effects through dual mechanisms: inhibiting VEGFR2 to suppress tumor angiogenesis and blocking PDGFRβ to disrupt tumor stromal support [1] 2. It shows better in vivo efficacy than the clinical VEGFR inhibitor sunitinib in A549 xenograft models (TGI: 75% vs. 58% at equivalent doses), likely due to its higher selectivity for VEGFR2/PDGFRβ [1] 3. In preclinical pancreatic cancer models, SKLB1002 reduces tumor hypoxia by inhibiting angiogenesis, which enhances the sensitivity of tumor cells to gemcitabine-based chemotherapy [2] |
Solubility Data
| Solubility (In Vitro) |
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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 (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 | 3.1212 mL | 15.6060 mL | 31.2120 mL | |
| 5 mM | 0.6242 mL | 3.1212 mL | 6.2424 mL | |
| 10 mM | 0.3121 mL | 1.5606 mL | 3.1212 mL |