Canertinib (CI-1033) is a potent and irreversible EGFR inhibitor that inhibits EGFR, HER2, and HER4 with IC50 values of 0.8, 19, and 7nM, respectively [1]. Canertinib decreases the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389, as well as the inactivation of downstream signaling molecules [2]. Canertinib has been widely used to inhibit tumor growth and induce ototoxicity in different preclinical models [3].
In vitro, Canertinib treatment for 72 hours significantly inhibited the proliferation of RaH3 cells and RaH5 cells, with IC50 values of 0.78μM and 0.80μM, respectively[4]. Canertinib treatment at 2μM for 72 hours significantly induced G1 phase cell cycle arrest and promoted cell apoptosis in HL-60 cells[5]. Canertinib treatment at 10μM for 6h significantly inhibited Akt and Erk1/2 phosphorylation and promoted PARP cleavage in Jurkat cells[6].
In vivo, Canertinib treatment via intraperitoneal injection at a dose of 80mg/kg/day for 4 days induced regression of FDC-P1/FLT3-ITD cells injected intravenously in transplanted mice[7]. Oral administration of Canertinib at a dose of 5mg/kg/day for 6 weeks significantly inhibited tumor growth in xenograft mice injected with CD63-BCAR4-overexpressing cells[8].
References:
[1] Ayati A, Moghimi S, Salarinejad S, et al. A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy[J]. Bioorganic chemistry, 2020, 99: 103811.
[2] Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies[J]. International journal of molecular sciences, 2014, 15(8): 13768-13801.
[3] Tang J, Qian Y, Li H, et al. Canertinib induces ototoxicity in three preclinical models[J]. Hearing research, 2015, 328: 59-66.
[4] Severinsson E A D, Trinks C, Gréen H, et al. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo[J]. Biochemical and Biophysical Research Communications, 2011, 414(3): 563-568.
[5] Trinks C, Djerf E A, Hallbeck A L, et al. The pan-ErbB receptor tyrosine kinase inhibitor canertinib induces ErbB-independent apoptosis in human leukemia (HL-60 and U-937) cells[J]. Biochemical and biophysical research communications, 2010, 393(1): 6-10.
[6] Trinks C, Severinsson E A, Holmlund B, et al. The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells[J]. Biochemical and biophysical research communications, 2011, 410(3): 422-427.
[7] Nordigården A, Zetterblad J, Trinks C, et al. Irreversible pan‐ERBB inhibitor canertinib elicits anti‐leukaemic effects and induces the regression of FLT3‐ITD transformed cells in mice[J]. British journal of haematology, 2011, 155(2): 198-208.
[8] Bae K, Kim J H, Lee J Y, et al. Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2[J]. Frontiers in Molecular Biosciences, 2022, 9: 952651.
Canertinib (CI-1033)是一种强效、不可逆的EGFR抑制剂，对EGFR、HER2和HER4的IC50值分别为0.8、19和7nM[1]。Canertinib可降低ErbB激酶信号靶点p70S6激酶T389的磷酸化，并使下游信号分子失活[2]。Canertinib已被广泛用于不同临床前模型中抑制肿瘤生长并诱导耳毒性[3]。
在体外，Canertinib处理72小时显著抑制了RaH3细胞和RaH5细胞的增殖，IC50值分别为0.78µM和0.80µM[4]。使用2µM的Canertinib处理72小时，显著诱导了HL-60细胞发生G1期细胞周期阻滞并促进了细胞凋亡[5]。使用10µM的Canertinib处理6小时，显著抑制了Jurkat细胞中Akt和Erk1/2的磷酸化，并促进了PARP的裂解[6]。
在体内，每日腹腔注射80mg/kg剂量的Canertinib，持续4天，诱导了移植小鼠中静脉注射的FDC-P1/FLT3-ITD细胞消退[7]。每日口服5mg/kg剂量的Canertinib，持续6周，显著抑制了注射过表达CD63-BCAR4细胞的异种移植小鼠中的肿瘤生长[8]。