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 . 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 .
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].
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.