Canertinib HCl
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MedKoo CAT#: 200600

CAS#: 289499-45-2 (HCl)

Description: Canertinib, also known as CI1033 and PD183805, is a potent ErbB inhibitor for the treatment of cancer. It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM). By 2015, Pfizer had discontinued development of the drug. Canertinib has been reported as a substrate for OATP1B3. Interaction of canertinib with OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Also, canertinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.


Chemical Structure

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Canertinib HCl
CAS# 289499-45-2 (HCl)

Theoretical Analysis

MedKoo Cat#: 200600
Name: Canertinib HCl
CAS#: 289499-45-2 (HCl)
Chemical Formula: C24H27Cl3FN5O3
Exact Mass:
Molecular Weight: 558.86
Elemental Analysis: C, 51.58; H, 4.87; Cl, 19.03; F, 3.40; N, 12.53; O, 8.59

Price and Availability

Size Price Availability Quantity
25.0mg USD 150.0 2 Weeks
50.0mg USD 250.0 2 Weeks
100.0mg USD 450.0 2 Weeks
200.0mg USD 750.0 2 Weeks
500.0mg USD 1250.0 2 Weeks
1.0g USD 1950.0 2 Weeks
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Related CAS #: 289499-45-2 (HCl)   267243-28-7 (free base)    

Synonym: CI1033; CI1033; CI-1033; PD183805; PD183805; PD183805; Canertinib HCl; Canertinib dihydrochloride

IUPAC/Chemical Name: N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy)quinazolin-6-yl)prop-2-enamide dihydrochloride

InChi Key: JZZFDCXSFTVOJY-UHFFFAOYSA-N

InChi Code: 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

SMILES Code: C=CC(NC1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1OCCCN4CCOCC4)=O.[H]Cl.[H]Cl

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: Canertinib dihydrochloride (CI-1033 dihydrochloride) is a potent and irreversible EGFR inhibitor; inhibits cellular EGFR and ErbB2 autophosphorylation with IC50s of 7.4 and 9 nM.
In vitro activity: Canertinib treatment of RaH3 and RaH5 with increasing concentrations (0–10 μM) for 72 h decreased the number of living cells in a dose-dependent manner (Fig. 1). Half-maximum growth inhibitory concentration (IC50), i.e. the dose required to inhibit serum stimulated growth by 50%, was estimated to 0.78 ± 0.08 μM in RaH3 and 0.80 ± 0.02 μM in RaH5. 5 μM canertinib completely inhibited growth (P < 0.01) and concentrations >5 μM induced dose-dependent cell death in both cell lines. Canertinib treatment of RaH3 and RaH5 cells with 1 μM for 24 h accumulated cells in the G1-phase of the cell cycle with a concomitant decrease in the S and G2/M cell cycle phase (Fig. 1C–F, Supplementary Table S1). Treatment of RaH3 and RaH5 cells with 10 μM of canertinib for up to 20 h decreased the number of cells in all cell cycle phases, also a time-dependent apoptotic sub-fraction of G1 cells appeared (Supplementary Fig. S1). Canertinib-induced apoptosis was confirmed by the Annexin V method, a time-dependent increase in apoptotic RaH3 and RaH5 cells occurred within 72 h of drug-exposure with 10 μM (Fig. 2C and D). Maximum apoptosis was achieved in RaH3 cells within 72 h (79%, P < 0.01) and in RaH5 cells within 48 h (76%, P < 0.001) of treatment (Fig. 2C and D). RaH3 and RaH5 cells treated with concentrations ⩾7.5 μM of canertinib for 48 h clearly induced apoptosis and with 10 μM apoptosis occurred in 56% (P < 0.05) and 76% (P < 0.001) of RaH3 and RaH5 cells, respectively (Fig. 2E and F). ErbB1 and ErbB3 phosphorylation was abolished within 30 min of 1 μM canertinib treatment of RaH3 and RaH5 and remained undetectable during the 6 h observation period as determined by Western blot (Fig. 3A). Canertinib treatment of RaH3 and RaH5 with 1 μM reduced Akt and Erk1/2 phosphorylation already within 30 min of incubation in both cell lines (Fig. 3B). Reference: Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8. https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(11)01733-5
In vivo activity: The growth of human malignant melanoma xenografts, RaH3 and RaH5, in nude mice was significantly inhibited by i.p. injections of 40 mg/kg/day canertinib (Fig. 4). The anti-proliferative effect on melanoma xenografts was visible already within 4 days of treatment and further increased throughout the treatment period as observed through the differences in tumor volumes, reaching statistical significance within 18 days of treatment (RaH3 P = 0.021 and RaH5 P = 0.014) (Fig. 4A and B). The growth inhibition of canertinib on RaH3 and RaH5 xenografts was also reflected by a significant decrease in tumor weights as compared to untreated tumors (Fig. 4C). The detectable side effects were mild including less than 8% weight loss in the treated mice compared to untreated animals, with no signs of skin rash, diarrhea or any other side effect, all animals seemed to thrive despite treatment. However, one RaH5 xenograft-bearing mouse died in the treatment group at day 5 without showing any signs of illness. Reference: Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8. https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(11)01733-5

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.0 89.47

Preparing Stock Solutions

The following data is based on the product molecular weight 558.86 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. Djerf Severinsson EA, Trinks C, Gréen H, Abdiu A, Hallbeck AL, Stål O, Walz TM. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8. doi: 10.1016/j.bbrc.2011.09.118. Epub 2011 Oct 1. PMID: 21982771. 2. Ako E, Yamashita Y, Ohira M, Yamazaki M, Hori T, Kubo N, Sawada T, Hirakawa K. The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo. Oncol Rep. 2007 Apr;17(4):887-93. doi: 10.3892/or.17.4.887. PMID: 17342332.
In vivo protocol: 1. Djerf Severinsson EA, Trinks C, Gréen H, Abdiu A, Hallbeck AL, Stål O, Walz TM. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8. doi: 10.1016/j.bbrc.2011.09.118. Epub 2011 Oct 1. PMID: 21982771. 2. Ako E, Yamashita Y, Ohira M, Yamazaki M, Hori T, Kubo N, Sawada T, Hirakawa K. The pan-erbB tyrosine kinase inhibitor CI-1033 inhibits human esophageal cancer cells in vitro and in vivo. Oncol Rep. 2007 Apr;17(4):887-93. doi: 10.3892/or.17.4.887. PMID: 17342332.

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1: Hassan W, Chitcholtan K, Sykes P, Garrill A. A Combination of Two Receptor Tyrosine Kinase Inhibitors, Canertinib and PHA665752 Compromises Ovarian Cancer Cell Growth in 3D Cell Models. Oncol Ther. 2016;4(2):257-274. doi: 10.1007/s40487-016-0031-1. Epub 2016 Sep 27. PubMed PMID: 28261654; PubMed Central PMCID: PMC5315083.

2: Tang J, Qian Y, Li H, Kopecky BJ, Ding D, Ou HC, DeCook R, Chen X, Sun Z, Kobel M, Bao J. Canertinib induces ototoxicity in three preclinical models. Hear Res. 2015 Oct;328:59-66. doi: 10.1016/j.heares.2015.07.002. Epub 2015 Jul 7. PubMed PMID: 26163095; PubMed Central PMCID: PMC4581429.

3: Minocha M, Khurana V, Qin B, Pal D, Mitra AK. Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib. Int J Pharm. 2012 Oct 15;436(1-2):127-34. doi: 10.1016/j.ijpharm.2012.05.038. Epub 2012 Jun 9. PubMed PMID: 22688250; PubMed Central PMCID: PMC3573846.

4: Djerf Severinsson EA, Trinks C, Gréen H, Abdiu A, Hallbeck AL, Stål O, Walz TM. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8. doi: 10.1016/j.bbrc.2011.09.118. Epub 2011 Oct 1. PubMed PMID: 21982771.

5: Nordigården A, Zetterblad J, Trinks C, Gréen H, Eliasson P, Druid P, Lotfi K, Rönnstrand L, Walz TM, Jönsson JI. Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice. Br J Haematol. 2011 Oct;155(2):198-208. doi: 10.1111/j.1365-2141.2011.08819.x. Epub 2011 Aug 16. PubMed PMID: 21848891.

6: Prasasya RD, Vang KZ, Kreeger PK. A multivariate model of ErbB network composition predicts ovarian cancer cell response to canertinib. Biotechnol Bioeng. 2012 Jan;109(1):213-24. doi: 10.1002/bit.23297. Epub 2011 Aug 23. PubMed PMID: 21830205; PubMed Central PMCID: PMC3786202.

7: Trinks C, Severinsson EA, Holmlund B, Gréen A, Gréen H, Jönsson JI, Hallbeck AL, Walz TM. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells. Biochem Biophys Res Commun. 2011 Jul 8;410(3):422-7. doi: 10.1016/j.bbrc.2011.05.148. Epub 2011 Jun 6. PubMed PMID: 21669187.

8: Trinks C, Djerf EA, Hallbeck AL, Jönsson JI, Walz TM. The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells. Biochem Biophys Res Commun. 2010 Feb 26;393(1):6-10. doi: 10.1016/j.bbrc.2010.01.055. Epub 2010 Jan 22. PubMed PMID: 20096663.

9: Galmarini CM. Canertinib pfizer. IDrugs. 2004 Jan;7(1):58-63. Review. PubMed PMID: 14730468.



Additional Information

Related:
289499-45-2 (Canertinib HCl sallt)
267243-28-7 (Canertinib free base).