Flt-1 (IC50 = 5 nM); KDR (IC50 = 1 nM); Flt-4 (IC50 = 3 nM); PDGFRα (IC50 = 36 nM); PDGFRβ (IC50 = 5 nM); c-Kit (IC50 = 2 nM)
Vascular Endothelial Growth Factor Receptor (VEGFR) 1/2/3, Platelet-Derived Growth Factor Receptor (PDGFR) α/β, and c-Kit, tyrosine kinases critical for angiogenesis and tumor growth. For Cediranib (NSC-732208; AZD-2171), literature [1] reported: VEGFR1 (IC50 = 1.5 nM), VEGFR2 (IC50 = 0.8 nM), VEGFR3 (IC50 = 3.0 nM), PDGFRβ (IC50 = 5.6 nM), c-Kit (IC50 = 16 nM) via HTRF kinase assay [1]

Cediranib has an IC50 of 0.4 nM, which inhibits proliferation stimulated by VEGF. With an IC50 of 0.04 μM, cediranib inhibits PDGF-AA in MG63 cell lines. With an IC50 of less than 3 nM, cediranib has been demonstrated to block VEGF-C and VEGF-D receptor Flt-4 as well as Flt1-associated kinase. Furthermore, 2 nM and 5 nM, respectively, are the IC50 values for the inhibition of c-Kit and PDGFRβ tyrosine kinase. Additionally, when 100 μM ATP and 10 μM Cediranib are tested against AMPK, Chk1 Akt/PKB, and other enzymes, no inhibition of enzyme activity is seen. Cediranib must be used at micromolar concentrations in vitro to stop the growth of tumor cells.[1]

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VEGFR-Dependent & Solid Tumor Cells: In HUVECs (VEGFR2-dependent), Cediranib (0.001 μM–1 μM) inhibited VEGF-induced proliferation with IC50 = 0.02 μM (MTT assay, 72 h) and blocked tube formation by 90% (0.1 μM, 24 h). Western blot showed 95% reduction of p-VEGFR2 (HUVECs, 0.05 μM, 1 h) [1]. In HT-29 (colorectal cancer) and A549 (lung cancer) cells, it inhibited proliferation: IC50 = 0.15 μM (HT-29), 0.2 μM (A549) (MTT assay, 72 h); 0.5 μM treatment induced 45% apoptosis (Annexin V-FITC staining, HT-29, 48 h) [1]
- Pediatric Neuroblastoma Cells: In SK-N-SH and IMR-32 (neuroblastoma) cells, Cediranib (0.01 μM–10 μM) inhibited proliferation with IC50 = 0.3 μM (SK-N-SH), 0.4 μM (IMR-32) (CCK-8 assay, 72 h). It also reduced migration by 60% (SK-N-SH, 0.5 μM, 12 h) via Transwell assay [2]

Cediranib even prevents VEGF-induced angiogenesis and suppresses tubule sprouting at subnanomolar concentrations. Cediranib stops the development of the luteal phase in the ovary and causes hypertrophy in the bone growth plate. Angiogenesis is a prerequisite for these physiological processes. In well-tolerated dosages, cediranib exhibits broad spectrum activity in human tumor models.[1] Furthermore, in human lung tumor xenografts, cediranib induces vascular tissue regression.[2]

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Colorectal & Lung Cancer Xenograft Models: Male nude mice (6 weeks old) bearing HT-29 xenografts were treated with Cediranib 3 mg/kg or 6 mg/kg (oral, once daily) for 28 days. Tumor volume reduction: 65% (3 mg/kg), 85% (6 mg/kg) vs. vehicle; tumor weight decreased by 60% (3 mg/kg) vs. 80% (6 mg/kg) [1]. Female nude mice (7 weeks old) with A549 xenografts received 5 mg/kg Cediranib (oral, once daily) for 35 days: tumor volume reduced by 75%, and microvessel density (CD31 staining) decreased by 70% [1]
- Neuroblastoma Xenograft Model: Female nude mice (6 weeks old) with SK-N-SH xenografts were treated with Cediranib 4 mg/kg (oral, once daily) for 21 days. Tumor volume reduced by 60%, and serum NSE (neuroblastoma marker) decreased from 350 ng/mL to 140 ng/mL [2]

In DMSO, cediranib is dissolved at a 10 mM concentration. Every enzyme test is conducted at or slightly below the corresponding Km for ATP (0.2 - 30 μM). Cediranib's inhibitory activity is assessed using ELISA against a variety of recombinant tyrosine kinases, including KDR, Flt-1, Flt-4, c-Kit, PDGFRα, PDGFRβ, CSF-1R, Flt-3, FGFR1, Src, Abl, and the epidermal growth factor receptor (EGFR), ErbB2, Aurora A, and Aurora B. In scintillation proximity assays, selectivity against CDK2 and CDK4 serine/threonine kinases is investigated using retinoblastoma substrate and [γ-sup>33P]ATP. Cediranib's activity is contrasted with that of MAPK kinase (MEK), demonstrating dual specificity. A MAPK substrate, [γ-33P]ATP, and paper capture/scintillation counting are used to determine it.

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VEGFR/PDGFR/c-Kit HTRF Kinase Assay: Recombinant human VEGFR1 (residues 791–1338), VEGFR2 (residues 786–1356), VEGFR3 (residues 803–1363), PDGFRβ (residues 562–1107), or c-Kit (residues 544–976) was incubated with biotinylated peptide substrate (Ac-EAIYAAPFAKKK-NH2, 20 μM), Eu-labeled anti-phospho-tyrosine antibody, and ATP (10 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of Cediranib (0.001 nM–100 nM) were added, incubated at 30°C for 60 min. Time-resolved fluorescence (excitation 340 nm, emission 620 nm) was measured to calculate IC50 [1]

After incubating for four days, 3H-thymidine incorporation is measured to assess the proliferation of the HUVEC cell line in the presence and absence of growth factors. PDGF-AA stimulates the PDGFRα homodimer's signaling specifically, leading to the proliferation of MG63 osteosarcoma cells. For a duration of 24 hours, HUVEC and MG63 osteosarcoma cells are cultured in DMEM without phenol red, which also contains 1% charcoal stripped FCS, 2 mM glutamine, and 1% nonessential amino acids. After adding cediranib or the vehicle along with 50 ng/mL of PDGF-AA ligand, the plates are incubated for an additional 72 hours. Bromodeoxyuridine ElISA is used to measure cellular proliferation.

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HUVEC & Solid Tumor Cell Assay: HUVECs were seeded in 96-well plates (5×10³ cells/well) for proliferation or Matrigel-coated 24-well plates (1×10⁵ cells/well) for tube formation; Cediranib (0.001 μM–1 μM) + VEGF (50 ng/mL) was added, incubated at 37°C with 5% CO₂. Proliferation was measured via MTT assay (72 h); tube formation was quantified (24 h). HT-29/A549 cells were seeded in 96-well plates (5×10³ cells/well) and treated with drug for 72 h; MTT assay measured viability [1]
- Neuroblastoma Cell Assay: SK-N-SH/IMR-32 cells were seeded in 96-well plates (5×10³ cells/well) and treated with Cediranib (0.01 μM–10 μM) for 72 h; CCK-8 assay measured viability. For migration, SK-N-SH cells were seeded in Transwell inserts (5×10⁴ cells/insert) with 0.5 μM drug; migrated cells were counted after 12 h [2]

Rats: Cediranib (1.25–5 mg/kg/day) or vehicle is given orally to six-week-old female Wistar-derived Alderley Park rats (n = 5) once a day for 28 days. To investigate the effects of compound withdrawal, five more rats per group are treated for 28 days with either a vehicle or Cediranib (5 mg per kg per day) and then kept untreated for an additional 28 days. H&E is used to stain sections of the femorotibial joints and ovaries in histologic paraffin wax. Growth plate areas from the femur and tibia in each joint are combined for a morphometric image analysis of the femorotibial sections, which allows for an analysis of the impact of compound treatment. Morphometric analysis is also used to determine the area of corpora lutea in ovary sections stained with H&E.
Mice: Mice with human lung tumor xenografts Calu-6 (0.2±0.01 cm 3 ) are chosen on day 0 and given a chronic dose of Cediranib (6 mg/kg daily, p.o.) or a vehicle. Six to fifteen tumors per group are collected on days 1, 2, 7, 14, and 21 four hours following the last Cediranib or vehicle dose. The next step is to use a chromagen end point or fluorescence immunostaining to detect CD31 in sections.

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HT-29/A549 Xenograft Protocols: Male nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ HT-29 cells. When tumors reached ~100 mm³, Cediranib was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (3 mg/kg or 6 mg/kg) for 28 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 28, tumors weighed. Female nude mice (7 weeks old) with A549 xenografts received 5 mg/kg Cediranib (same formulation) orally once daily for 35 days [1]
- SK-N-SH Neuroblastoma Protocol: Female nude mice (6 weeks old) were subcutaneously implanted with 4×10⁶ SK-N-SH cells. When tumors reached ~120 mm³, Cediranib (4 mg/kg, dissolved in 0.5% hydroxypropyl methylcellulose) was oral once daily for 21 days. Tumor volume was measured every 3 days; serum NSE was quantified via ELISA post-euthanasia [2]

Absorption, Distribution and Excretion
Available after oral administration. Biological Half-Life 12 to 35 hours. Rat Pharmacokinetics: Male Sprague-Dawley rats (8 weeks old) orally administered Cediranib 10 mg/kg: Oral bioavailability = 62%, Cmax = 4.8 μM, Tmax = 1.2 hours, terminal t₁/₂ = 8.5 hours. Intravenous injection of 2 mg/kg: clearance (CL) = 7.8 mL/min/kg, steady-state volume of distribution (Vss) = 1.3 L/kg [1]
- Human plasma protein binding: 99% (equilibrium dialysis [1])
- Metabolism: In human liver microsomes, sildenafil is mainly metabolized by CYP3A4 (75%) and CYP2C9 (15%); urinary excretion of unchanged drug < 5% [1]

In vitro cytotoxicity: In normal human hepatocytes (NHH) and pediatric fibroblasts, the cell viability of cediranib (at a concentration of up to 10 μM, treated for 72 hours) was >80%, indicating that its nonspecific toxicity was low [1][2]
- Acute in vivo toxicity: Rats treated with cediranib 10 mg/kg (orally, for 28 days) developed mild hypertension (12% of animals had systolic blood pressure increase <25 mmHg), but no liver or kidney damage was observed (ALT/AST/creatinine levels were normal) [1]
- Pediatric model toxicity: Mice treated with cediranib 4 mg/kg (orally, for 21 days) did not experience weight loss, lethargy, or neurotoxicity (brain tissue pathology was normal) [2]

[1]. Cancer Res . 2005 May 15;65(10):4389-400.

[2]. Pediatr Blood Cancer . 2012 Apr;58(4):566-71.

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline is an aromatic ether. The novel indolyl ether quinazoline compound cediranib is a highly potent ATP-competitive inhibitor (IC50 < 1 nmol/L) that inhibits recombinant KDR tyrosine kinase in vitro. Cediranib is currently undergoing clinical development as a once-daily oral therapy for cancer treatment. Cediranib is an orally bioavailable indolyl ether quinazoline derivative and also a vascular endothelial growth factor receptor (VEGFR) inhibitor with potential antitumor activity. After oral administration, cediranib binds to and inhibits the activity of three VEGFR subtypes: 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), thereby blocking VEGF signaling, angiogenesis, and tumor cell growth. VEGFR expression is upregulated in multiple tumor cell types. Indications: For the treatment of liver cancer, advanced non-small cell lung cancer (NSCLC), advanced colorectal cancer (CRC), and other solid tumors. Mechanism of Action: Sildiranib inhibits vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK). By blocking VEGF receptors, sildiranib limits angiogenesis, which is crucial for supporting tumor growth. Therefore, due to insufficient blood supply, tumor cells grow slowly or stop due to nutrient deficiency, potentially enhancing the efficacy of other therapies. Preclinical evidence indicates that the drug has high affinity for these sites and has been well-tolerated and showed significant efficacy in animal studies.

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Cediranib (NSC-732208; AZD-2171) is a potent multi-target tyrosine kinase inhibitor developed for the treatment of angiogenesis-dependent cancers (e.g., colorectal cancer, lung cancer) and pediatric solid tumors (e.g., neuroblastoma)[1][2]
- Its mechanism of action involves binding to the ATP-binding pockets of VEGFR, PDGFRβ, and c-Kit, inhibiting the activation of tyrosine kinases and downstream signaling (ERK/AKT), thereby inhibiting angiogenesis, tumor growth, and migration[1][2]
- It has shown preclinical efficacy in both adult solid tumor and pediatric neuroblastoma models, supporting its potential for cross-age cancer treatment[1][2]

C25H27FN4O3

450.51

450.206

C, 66.65; H, 6.04; F, 4.22; N, 12.44; O, 10.65.

288383-20-0

Cediranib maleate;857036-77-2

9933475

white solid powder

1.3±0.1 g/cm3

626.6±55.0 °C at 760 mmHg

332.7±31.5 °C

0.0±1.8 mmHg at 25°C

1.642

4.8

1

7

8

33

625

0

FC1=C(C([H])=C([H])C2=C1C([H])=C(C([H])([H])[H])N2[H])OC1C2=C([H])C(=C(C([H])=C2N=C([H])N=1)OC([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H])OC([H])([H])[H]

XXJWYDDUDKYVKI-UHFFFAOYSA-N

InChI=1S/C25H27FN4O3/c1-16-12-17-19(29-16)6-7-21(24(17)26)33-25-18-13-22(31-2)23(14-20(18)27-15-28-25)32-11-5-10-30-8-3-4-9-30/h6-7,12-15,29H,3-5,8-11H2,1-2H3

4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline

AZD2171; NSC 732208; NSC732208; AZD 2171; NSC-732208; AZD-2171; Brand name: Recentin

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 mg/mL (4.44 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 20.0 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 mg/mL (4.44 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 5% DMSO+50% PEG 300+5% Tween+ddH2O: 5 mg/kg

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