The HER family of receptor tyrosine kinases, EGFR, HER2, HER3, and HER4, mediate proliferation, migration, adhesion, differentiation, and survival in many different cell types and have been implicated in the development and progression of a variety of human tumors.Canertinib dihydrochloride is an irreversible quinazoline-based HER family tyrosine kinase inhibitor with IC50 values of 0.8, 19, and 7 nM for blocking in vitro activity of EGFR, HER2, and HER4, respectively. As a broadly applicable anti-cancer agent, it has been used to suppress proliferation of malignant peripheral nerve sheath tumor cells (effective concentration of 250-500 nM), to inhibit growth and induce dose-dependent apoptosis in a panel of neuroblastoma cell lines (IC50s = 0.94-2.45 μM), and to reduce proliferation of acute myeloid leukemia cells (IC50 = 0.27 μM). Canertinib dihydrochloride also displays anti-neoplastic activity towards T98G glioblastoma cells, HCT8 colorectal carcinoma cells, and cells expressing the breast cancer resistance protein.
CI-1033 is a potent inhibitor of EGFR and ErbB2 with IC50 of 1.5 nM and 9.0 nM, respectively.
Canertinib Dihydrochloride is a water-soluble, EGFR, HER2, and ErbB-4 tyrosine kinase inhibitor.
CI-1033 is a potent, irreversible ATP binding site–directed pan-ErbB tyrosine kinase inhibitor with IC50 in the low nanomolar range for EGFR, HER2, and ErbB-4.
4-Chloro-7-fluoroquinazoline was prepared by nitration to produce 4-chloro-7-fluoro-6-nitroquinazoline, which was then condensed with 3-chloro-4-fluoroaniline, substituted with 3-(4-morpholino)-1-propanol, aminoprotected reduction with ethyl trifluoroacetate, Raney Ni catalyzed hydrogenation, and then condensed with acrylic acid, deprotected to obtain the antitumor agent canutinib dihydrochloride in a total yield of about 70%.
Canertinib dihydrochloride (CI-1033 dihydrochloride) shows superior in vivo antitumor activity, giving growth delays in A431 xenografts exceeding 50 days following oral administration[1]. The growth of human malignant melanoma xenografts, RaH3 and RaH5, in nude mice is significantly inhibited by i.p. injections of 40 mg/kg/day canertinib (Fig. 4). The anti-proliferative effect on melanoma xenografts is 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[2].
EGFR: 7.4 nM (IC50); ErbB2: 9 nM (IC50)
