Sunday, September 27, 2015

Drugs in Clinical Pipeline: Canertinib

Canertinib [N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy) quinazolin-6-yl)prop-2-enamide] is an orally bio-available quinazoline compound with potential antineoplastic and radiosensitizing activities. Canertinib binds to the intracellular domains of epidermal growth factor receptor tyrosine kinases (ErbB family), irreversibly inhibiting their signal transduction functions and resulting in tumor cell apoptosis and suppression of tumor cell proliferation. This agent also acts as a radiosensitizing agent and displays synergistic activity with other chemotherapeutic agents.

Canertinib is a novel tyrosine kinase inhibitor developed for the treatment of certain solid cancers and has been designed to specifically inhibit all member of the ERBB-receptor family (ERBB1, ERBB2, ERBB3 and ERBB4) without blocking tyrosine kinase activity of many other receptors such as platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and insulin receptor (INSR) [1].

It is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 = 1.5 nM) and ErbB-2 (IC50 = 9.0 nM) [2].

The activity of Canertinib is as follows: 

IC50 (EGFR cell-free assay) = 1.5 nM
IC50 (ErbB2 cell-free assay) = 9.0 nM

Common Name: Canertinib
Synonyms:  CI-1033; PD183805
IUPAC Name: N-(4-((3-Chloro-4-fluorophenyl)amino)-7-(3-(morpholin-4-yl)propoxy) quinazolin-6-yl)prop-2-enamide
CAS Number: 267243-28-7; 289499-45-2 (hydrochloride)
Mechanism of Action: Kinase Inhibitor; EGFR Inhibitor; ErbB2 Inhibitor; pan-ERBB Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Phase III
Company: Pfizer, Inc.
Canertinib, was designed as a pan-ERBB tyrosine kinase inhibitor. It inhibits all four ERBB receptor family members. Canertinib is an irreversible inhibitor that binds covalently to specific cysteine residues in the ATP-binding pocket such as cysteine 773 of EGFR, cysteine 784 of ERBB2 and cysteine 778 of ERBB4 thereby blocking the ATP binding site in the kinase domain of ERBB proteins, preventing their kinase activity and downstream signaling, it also prevents transmodulation of ERBB3 [3]. The covalent binding of canertinib results in prolonged suppression of ERBB activity [4]. Since canertinib blocks signaling through all members of the ErbB receptor family it is more efficient and has a broader antitumor effect than inhibitors that only prevent signaling from one of the ErbB receptors. Studies of human cancer cell lines indicate that canertinib results in potent and sustained inhibition of ERBB tyrosine kinase activity, thereby inhibition of Akt and MAPK pathways [5, 6]. Canertinib has been shown to inhibit growth and induce apoptosis in several cancer cell lines and xenografts [7, 8, 9]. It increases the effectiveness of radiation therapy [8]. In clinical studies canertinib has been shown to have acceptable side-effects. However, in phase II studies canertinib was only able to show modest effects on breast cancer and NSCLC patients [10, 11].
Canertinib is evaluated in clinical trials in the treatment of different solid cancers. Canertinib seems to be a promiscuous drug, a multi-kinase inhibitor, which is able to bind not only to the ERBB receptor family, but also to intracellular proteins. For instance, the Src kinase family consists of eight members, five of which are mainly expressed in hematopoeitic cells, Blk, Hck, Lck, Fyn, and Lyn, where the Lck protein seems to have a stronger binding to canertinib as shown in a protein binding assay [12].
Canertinib not only inhibits tyrosine phosphorylation but also enhances ubiquitinylation and accelerates endocytosis and subsequent intracellular destruction of ErbB-2 molecules. It alkylates a cysteine residue specific to ErbB receptors. The degradative pathway of ErbB receptor tyrosine kinases stimulated by tyrosine kinase inhibitors appears to be chaperone mediated, and thus is similar to the pathways activated by the heat shock protein 90 (Hsp90) antagonist geldanamycin and by stress-induced mechanisms [13].
It prevents smallpox viral replication in vitro and inhibits smallpox viral infection in vivo. [14]
Canertinib inhibited erbB receptor phosphorylation and induced growth inhibition and apoptosis at concentrations of 1 uM or more [15]
Canertinib has been demonstrated to increase the anti-proliferative effects of vemurafenib in the BRAF mutant melanoma cell lines, but little or no enhanced effect was noted with the combination treatment in the wild type melanoma cell lines [16].
Canertinib decreased the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 in a dose-dependent manner as well as inactivation of downstream signaling molecules in ALL cell lines. Canertinib also increased the expression of the pro-apoptotic protein BIM, caspase-3 cleavage followed by apoptosis, abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs [17].
Several clinical trials are testing the anti-tumor activity of canertinib in metastatic breast cancer [10], NSCLC [11] and advanced ovarian cancer [18].
1. Slichenmyer, W. J.; et. al. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin. Oncol. 2001, 28(5 Suppl 16), 80-85.
2. Smaill, J. B.; 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.
3. Fry, D. W., et. al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1998, 95(20), 12022-12027.
4. Smaill, J. B.; et. al. Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor. J. Med. Chem. 1999, 42(10), 1803-1815.
5. Djerf, E. A.; et. al. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839). Melanoma Res, 2009, 19(3), 156-166.
6. Djerf Severinsson, E. A.; et. al. 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. 414(3), 563-568.
7. 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.
8. Nyati, M. K.; et. al. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Clin. Cancer Res 2004. 10(2), 691-700.;
9. Slichenmyer, W. J.; et. al. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol, 2001, 28(5 Suppl 16), 80-85.
10. Rixe, O.; et al. A randomized, phase II, dose-finding study of the pan-ErbB receptor tyrosine-kinase inhibitor CI-1033 in patients with pretreated metastatic breast cancer. Cancer Chemother. Pharmacol. 2009, 64(6), 1139-1148.
11. Janne, P. A.; et. al. Multicenter, randomized, phase II trial of CI-1033, an irreversible pan-ERBB inhibitor, for previously treated advanced non smallcell lung cancer. J. Clin. Oncol. 2007, 25(25), 3936-3944.
12. Fabian, M. A.; et. al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 2005, 23(3), 329-336.
13. Citri, A.; et. al. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO J. 2002, 21(10), 2407-2417.
14. Fauci, A. S.; et. al. Host-based antipoxvirus therapeutic strategies: turning the tables. J. Clin. Invest. 2005, 115(2), 231-233.
15. Hughes, D. P.; et. al. Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition. Pediatr. Blood Cancer. 2006, 46(5), 614-623.
16. Ng, Y. K.; et. al. Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res. 201424(3), 207-218.
17. Irwin, M. E.; et. al. Small molecule ErbB inhibitors decrease proliferative signaling and promote apoptosis in philadelphia chromosome-positive acute lymphoblastic leukemia. PLoS One 20138(8), e70608.
18. Campos, S.; et. al. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J. Clin. Oncol. 200523(24), 5597-5604.
19. Ciardiello, F.; et. al. novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin. Cancer Res. 20017(10), 2958-2970.