Canertinib HCl | CI-1033 | CAS#289499-45-2 | | EGFR inhibitor

MedKoo Cat#: 200600 | Name: Canertinib HCl

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

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: 0.0000

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
10mg	USD 250.00	2 Weeks
25mg	USD 450.00	2 Weeks
50mg	USD 750.00	2 Weeks
100mg	USD 1,250.00	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

More Info

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

Product Data

Product Data

Instruction

View handling instruction

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

	Solvent	mg/mL	mM
Solubility
	DMSO	50.0	89.47

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

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.

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

Formulation protocol:

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: Galmarini CM. Canertinib pfizer. IDrugs. 2004 Jan;7(1):58-63. PMID: 14730468. 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. PMID: 26163095; PMCID: PMC4581429. 3: Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic A. Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol. 2015 Feb;72(2):203-18; quiz 219-20. doi: 10.1016/j.jaad.2014.07.032. PMID: 25592338. 4: Gomaa HAM, Ali AT, Gabbar MA, Kandeil MA. The Effect of Canertinib on Sensitivity of Cytotoxic Drugs in Tamoxifen-Resistant Breast Cancer Cells In Vitro. Int J Genomics. 2018 Oct 23;2018:7628734. doi: 10.1155/2018/7628734. PMID: 30425998; PMCID: PMC6218737. 5: 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. PMID: 21669187. 6: 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. 7: 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. PMID: 21848891. 8: Aydinlik S, Dere E, Ulukaya E. Induction of autophagy enhances apoptotic cell death via epidermal growth factor receptor inhibition by canertinib in cervical cancer cells. Biochim Biophys Acta Gen Subj. 2019 May;1863(5):903-916. doi: 10.1016/j.bbagen.2019.02.014. Epub 2019 Feb 27. PMID: 30825616. 9: 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. PMID: 20096663. 10: von Manstein V, Groner B. Tumor cell resistance against targeted therapeutics: the density of cultured glioma tumor cells enhances Stat3 activity and offers protection against the tyrosine kinase inhibitor canertinib. Medchemcomm. 2016 Oct 14;8(1):96-102. doi: 10.1039/c6md00463f. PMID: 30108694; PMCID: PMC6072326. 11: 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. PMID: 28261654; PMCID: PMC5315083. 12: 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. PMID: 22688250; PMCID: PMC3573846. 13: Baselga J, Hammond LA. HER-targeted tyrosine-kinase inhibitors. Oncology. 2002;63 Suppl 1:6-16. doi: 10.1159/000066198. PMID: 12422050. 14: Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science. 2017 Mar 17;355(6330):1163-1167. doi: 10.1126/science.aam7340. Epub 2017 Mar 16. PMID: 28302825. 15: 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. PMID: 21830205; PMCID: PMC3786202. 16: Ng YK, Lee JY, Supko KM, Khan A, Torres SM, Berwick M, Ho J, Kirkwood JM, Siegfried JM, Stabile LP. Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res. 2014 Jun;24(3):207-18. doi: 10.1097/CMR.0000000000000060. PMID: 24709886; PMCID: PMC4394744. 17: Bae K, Kim JH, Lee JY, Kong SY, Kim YH, Kim S, Yoon KA. Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2. Front Mol Biosci. 2022 Aug 23;9:952651. doi: 10.3389/fmolb.2022.952651. PMID: 36081848; PMCID: PMC9445485. 18: Zomerman WW, Plasschaert SL, Diks SH, Lourens HJ, Meeuwsen-de Boer T, Hoving EW, den Dunnen WF, de Bont ES. Exogenous HGF Bypasses the Effects of ErbB Inhibition on Tumor Cell Viability in Medulloblastoma Cell Lines. PLoS One. 2015 Oct 23;10(10):e0141381. doi: 10.1371/journal.pone.0141381. PMID: 26496080; PMCID: PMC4619778. 19: Katiyar S, Kufareva I, Behera R, Thomas SM, Ogata Y, Pollastri M, Abagyan R, Mensa-Wilmot K. Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds. PLoS One. 2013;8(2):e56150. doi: 10.1371/journal.pone.0056150. Epub 2013 Feb 20. Erratum in: PLoS One. 2014;9(3):e92488. PMID: 23437089; PMCID: PMC3577790. 20: Rocha-Lima CM, Soares HP, Raez LE, Singal R. EGFR targeting of solid tumors. Cancer Control. 2007 Jul;14(3):295-304. doi: 10.1177/107327480701400313. PMID: 17615536.