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)

SMILES:C=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4.Cl.Cl 

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].

References:

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.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. 2014, 24(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 2013, 8(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. 2005, 23(24), 5597-5604.

19. Ciardiello, F.; et. al. novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor. Clin. Cancer Res. 2001, 7(10), 2958-2970.

Drugs in Clinical Pipeline: Pelitinib

Pelitinib [(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide] is a 3-cyanoquinoline bearing  irreversible inhibitor of pan-ErbB tyrosine kinases. It is an orally active, potent and belongs to second generation of inhibitors. Pelitinib forms irreversible covalent bonds with epidermal growth factor receptors (EGFR) ErbB-1, -2 and -4, thereby inhibiting receptor phosphorylation and signal transduction and resulting in apoptosis and suppression of proliferation in EGFR-overexpressing tumor cell lines.

Pelitinib inhibits EGFR activity with the half maximal inhibition concentration IC₅₀ value of 38.5 nM in vitro [1]. It has been found to exert a potent anti-proliferative activity against tumor cells overexpressing EGFR, including NHEK, A431 and MDA-468 cells, with IC₅₀ values of 61 nM, 125 nM and 260 nM respectively; while it has also been found to potently inhibit EGF-induced phosphorylated EGFR (pEGFR) in A431 and NHEK cells with IC₅₀ values ranging from 20 nM to 80 nM [2].

The activity of Pelitinib is as follows:

IC₅₀ (EGFR enzyme assay) = 38.5 nM

IC₅₀ (SRC enzyme assay) = 282 nM

IC₅₀ (MEK/ERK enzyme assay) = 800 nM

IC₅₀ (ErbB2 enzyme assay) = 1.255 uM

IC₅₀ (Raf enzyme assay) = 3.353 uM

IC₅₀ (c-Met enzyme assay) = 4.1 uM

IC₅₀ (CDK4 enzyme assay) = greater than 20 uM

Common Name: Pelitinib

Synonyms:  EKB 569; EKB-569; WAY-EKB 569; WAY-EKB-569; WAY-172569

IUPAC Name: (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide

CAS Number: 257933-82-7

SMILES: CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)F)Cl)C#N) NC(=O)/C=C/CN(C)C

Mechanism of Action: Kinase Inhibitor; pan-ErbB Inhibitor; EGFR Inhibitor

Indication: Advanced Non-small Cell Lung Cancer; Colorectal Cancer

Development Stage: Phase II

Company: Wyeth / Pfizer

The epidermal growth factor receptor (EGFR) is a 170-kDa glycoprotein containing an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. EGFR is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB2), Her3 (ErbB-3) and Her4 (ErbB-4). On binding ligands, such as EGF or transforming growth factor-alpha (TGF-alpha), EGFR dimerizes with itself (homodimerization) or other members of the family such as c-erbB-2 (heterodimerization). Tyrosine kinase activity increases and the receptor phosphorylates tyrosine residues on itself (autophosphorylation). Phosphorylated EGF-R (pEGF-R), like other activated receptor tyrosine kinases, phosphorylates and activates several signal transduction pathways downstream of EGF-R, including phosphoinositide 3-kinase-AKT, extracellular signal-regulated kinase 1 and 2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) pathways that ultimately control cell proliferation [3,4].

Mutations affecting EGFR expression or activity could result in cancer. Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers and glioblastoma multiforme. The somatic mutations involving EGFR leads to its constant activation, which produces uncontrolled cell division. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

Pelitinib or EGFR kinase inhibitor 86 irreversibly inhibits ErbB1 and ErbB2 by forming a covalent bond with Cys773 of the ATP-pocket. Since Pelitinib is very specific and water soluble, it has good bioavailability and specific reactivity towards its target, and therefore exerts potent anti-tumor effects and causes few side effects. Apart from inhibiting the EGFR kinase, it also displays activity towards HER2 in BT474 cell line. Reports of its use in solid tumors indicated that Pelitinib was well tolerated and had an acceptable pharmacokinetic safety profile. Toxicities associated with Pelitinib treatment were of gastrointestinal and sometimes of dermatological origin. A phase I-II dose-escalation study of Pelitinib in combination with chemotherapy FOLFOX4 and FOLFIRI pointed to some additional toxicities, including thrombocytopenia, and in cases of high doses haematological toxicities and neuropathy. But the overall responses were good as in the majority of the cases either complete or partial responses or stable disease was noted, although a minority showed signs of progressive disease as well. Currently, phase II studies in advanced colorectal cancers and combination studies of CCI-779 and Celecoxib in combination with Pelitinib are being set up to evaluate the potency of Pelitinib at a larger scale [5-9].

References:

1. Torrance, C. J.; et. al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000, 6(9), 1024-1028.

2. Nunes, M.; et. al. Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther 2004, 3(1), 21-27.

3. Arteaga, C. L. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 2001, 19(18), 32S-40S.

4. Schlessinger, J. Cell signalling by receptor tyrosine kinases. Cell 2000, 103(2), 211-225.

5. Fabian, M. A.; et. al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005, 23(3), 329-336.

6. Tsou, H. R.; et. al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 2005, 48(4), 1107-1131.

7. Hidalgo, M.; et. al. Phase I trials of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 2006, 24(15), 2252-2260.

8. Bonomi, P. Clinical studies with non-iressa EGFR tyrosine kinase inhibitors. Lung Cancer 2003, 41, S43-S48.

9. Tejpar, S.; et. al. Toxicity profile of the epidermal growth factor receptor inhibitor EKB-569 combined with fluoroacil-based chemotherapy in patients with advanced colorectal cancer. Cancer Abstr Summaries 2004, 5.

10. Tyner, J. W.; et. al. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-3 transdifferentiation signals. J Clin Invest 2006, 116(2), 309-321.

11. Tejpar, S.; et. al. Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC). Proc Am Soc Clin Oncol 2004, 3579.

12. Casado, E.; et. al. A phase I/IIA pharmacokinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients with advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 2004, 3543.