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CP-547632 (PAN-90806), a novel isothiazole, is a novel, orally bioavailable and ATP-competitive inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases with IC50s of 11 nM and 9 nM, respectively. It exhibits selectivity in comparison to other related TKs such as platelet-derived growth factor beta and epidermal growth factor receptor. Additionally, in a whole cell assay, it inhibits VEGF-stimulated autophosphorylation of VEGFR-2 at an IC(50) value of 6 nM. VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent manner (EC(50) = 590 ng/ml) following oral administration of CP-547,632 to mice harboring NIH3T3/H-ras tumors. These concentrations of plasma showed a strong correlation with the measured levels of the substance required to prevent VEGF-induced corneal angiogenesis in BALB/c mice. CP-547,632 is a compound that potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. The inhibitory activities of this compound were directly compared against FGF receptor 2 or VEGFR-2 using a sponge angiogenesis assay. After giving this medication once daily intraperitoneally to athymic mice carrying human xenografts, the antitumor efficacy was assessed and showed up to 85% tumor growth inhibition. A well-tolerated, orally bioavailable inhibitor called CP-547,632 is currently being studied in clinical trials to treat cancers in humans.
Physicochemical Properties
| Molecular Formula | C20H24BRF2N5O3S |
| Molecular Weight | 532.40206 |
| Exact Mass | 531.075 |
| Elemental Analysis | C, 45.12; H, 4.54; Br, 15.01; F, 7.14; N, 13.15; O, 9.02; S, 6.02 |
| CAS # | 252003-65-9 |
| Related CAS # | CP-547632 hydrochloride;252003-71-7;CP-547632 TFA;2805804-54-8 |
| PubChem CID | 9811611 |
| Appearance | White to light yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 548.6±50.0 °C at 760 mmHg |
| Flash Point | 285.6±30.1 °C |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
| Index of Refraction | 1.622 |
| LogP | 3.69 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 10 |
| Heavy Atom Count | 32 |
| Complexity | 622 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(NC1=C(C(N)=O)C(OCC2=C(F)C=C(Br)C=C2F)=NS1)NCCCCN3CCCC3 |
| InChi Key | HXHAJRMTJXHJJZ-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C20H24BrF2N5O3S/c21-12-9-14(22)13(15(23)10-12)11-31-18-16(17(24)29)19(32-27-18)26-20(30)25-5-1-2-6-28-7-3-4-8-28/h9-10H,1-8,11H2,(H2,24,29)(H2,25,26,30) |
| Chemical Name | 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide |
| Synonyms | PAN90806; PAN 90806; PAN-90806; CP547632; CP 547632; CP-547632; CP632; OSI632; CP 632; OSI 632; CP-632; OSI-632 |
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 | VEGFR-2 (IC50 = 11 nM); FGFR (IC50 = 9 nM) |
| ln Vitro | CP-547632 (1-1000 nM; 1 hour) has an IC50 value of 6 nM and suppresses VEGF-stimulated VEGFR-2 phosphorylation in a dose-dependent manner [1]. |
| ln Vivo | CP-547632 (1-1000 nM; 1 hours)inhibits VEGF-stimulated VEGFR-2 phosphorylation in a dose-dependent manner, with an IC50 value of 6 nM[1]. |
| Enzyme Assay | CP-547632 (p.o.; 6.25-100 mg/kg/day; for 10-24 days) nhibits Colo-205, DLD-1, and MDA-MB-231 xenografts' ability to grow in a dose-dependent manner[1]. For 12 hours, plasma concentrations of CP-547632 (oral; 50 mg/kg; single oral dose) are greater than 500 ng/ml[1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: Serum-depleted Cell Tested Concentrations: 1, 4, 16, 63, 250, 1000 nM Incubation Duration: 1 hour Experimental Results: Inhibits VEGF-stimulated VEGFR-2 phosphorylation in a dose-dependent manner. |
| Animal Protocol |
Athymic female mice (CD-1 nu/nu) bearing tumors (75-150 mm in size)[1] 6.25, 12.5, 25, 50, 100 mg/kg PO; daily; 10-24 days |
| References |
[1]. Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res. 2003 Nov 1;63(21):7301-9. |
| Additional Infomation | CP-547632 has been used in trials studying the treatment of Ovarian Cancer, Lung Neoplasms, Ovarian Neoplasms, Peritoneal Neoplasms, and Fallopian Tube Cancer, among others. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~100 mg/mL (~187.8 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 4 mg/mL (7.51 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 40.0 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. Solubility in Formulation 2: 4 mg/mL (7.51 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 40.0 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. Solubility in Formulation 3: ≥ 4 mg/mL (7.51 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 40.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8783 mL | 9.3914 mL | 18.7829 mL | |
| 5 mM | 0.3757 mL | 1.8783 mL | 3.7566 mL | |
| 10 mM | 0.1878 mL | 0.9391 mL | 1.8783 mL |