Canertinib (CI-1033, PD-183805)

• CAT Number: I002998
• CAS Number: 289499-45-2
• Molecular Formula: C₂₄H₂₅ClFN₅O₃ . 2HCl
• Molecular Weight: 558.86
• Purity: ≥95%
• Target: HER2
• Solubility: DMSO:>10 mg/mL; water: >10 mg/mL
• Storage: Store at -20°C
• IC50: 1.5/0.9 nM(EGFR/ErbB2) [1]
• InChI: InChI=1S/C24H25ClFN5O3.2ClH/c1-2-23(32)30-21-13-17-20(14-22(21)34-9-3-6-31-7-10-33-11-8-31)27-15-28-24(17)29-16-4-5-19(26)18(25)12-16;;/h2,4-5,12-15H,1,3,6-11H2,(H,30,32)(H,27,28,29);2*1H
• InChIKey: JZZFDCXSFTVOJY-UHFFFAOYSA-N
• SMILES: C=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4.Cl.Cl

Canertinib 2Hcl (CI-1033; PD-183805) is a pan-ErbB inhibitor for EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, no activity to PDGFR, FGFR, InsR, PKC, or CDK1/2/4.IC50 value: 1.5/0.9 nM(EGFR/ErbB2) [1]Target: EGFR/ErbB2in vitro: CI-1033 shows excellent potency for irreversible inhibition of erbB2 autophosphorylation in MDA-MB 453 cells. CI-1033 also shows high permeability in Caco-2 cells and inhibits secretory transport of vinblastine, which indicates that CI-1033 is a likely inhibitor of the P-gp [1]. CI-1033 alone, significantly suppresses constitutively activated Akt and MAP kinase. In combination with gemcitabine, CI-1033 inhibits Akt and prevents increased levels of MAPK phosphorylation. CI-1033 stimulates p27 expression and p38 phosphorylation in MDA-MB-453 cells [2]. CI-1033 is highly specific to the erbB receptor family and not sensitive to PGFR, FGFR or IR even at 50 μM. CI-1033 shows high levels of inhibition in A431 cells expressing EGFR with IC50 of 7.4 nM. CI-1033 suppresses heregulin-stimulated tyrosine phosphorylation of erbB2, erbB3 and erbB4 with IC50 of 5, 14 and 10 nM, respectively. CI-1033 also inhibits expression of pp62c-fos in response to heregulin [3].in vivo: CI-1033 shows impressive activity against A431 xenografts in nude mice at 5 mg/kg of body weight [1]. CI-1033 (20 to 80 mg/kg/d) achieves a high degree of tumor regressions in H125 xenograft models [3]. Oral administration of CI-1033 causes a marked inhibition of growth in TT, TE6 and TE10 xenografts in nude mice, without animal death and <10% weight loss [4].

Reference

[1]. Smaill JB et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000; 43(7): 1380-1397.
[2]. Nelson JM et al. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem. 2001; 276(18): 14842-14827.
[3]. Slichenmyer WJ et al. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol. 2001; 28(5 Suppl 16): 80-85.
[4]. Ako E, et al. The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo. Oncol Rep. 2007; 17(4): 887-893.