Pelitinib

• CAT Number: I002877
• CAS Number: 257933-82-7
• Molecular Formula: C24H23ClFN5O2
• Molecular Weight: 467.92
• Purity: ≥95%
• Synonyms: (E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
• InChI: InChI=1S/C24H23ClFN5O2/c1-4-33-22-12-20-17(11-21(22)30-23(32)6-5-9-31(2)3)24(15(13-27)14-28-20)29-16-7-8-19(26)18(25)10-16/h5-8,10-12,14H,4,9H2,1-3H3,(H,28,29)(H,30,32)/b6-5+
• InChIKey: WVUNYSQLFKLYNI-AATRIKPKSA-N
• SMILES: CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)F)Cl)C#N)NC(=O)C=CCN(C)C

Pelitinib (EKB-569;WAY-EKB 569) is an irreversible inhibitor of EGFR with an IC50 of 38.5 nM; also slightly inhibits Src, MEK/ERK and ErbB2 with IC50s of 282, 800, and 1255 nM, respectively.
Pelitini has much greater inhibitory activity against the EGFR kinase than against Src, MEK/ERK, Cdk4, c-Met, Raf and ErbB2, for example, the IC50 for EGFR is 32-fold lower than the IC50 for the closely related ErbB2. Pelitinib results in a dramatic reduction in EGFR phosphorylation but no change in the total amount of EGFR protein. It requires at least 10-fold more drug to equivalently inhibit ErbB2 phosphorylation in similar assays, and EKB-569 does not block phosphorylation of another receptor tyrosine kinase (c-Met) assessed in the same manner[1]. EKB-569 is a potent inhibitor of proliferation in NHEK, A431, and MDA-468 cells (IC50=61, 125, and 260 nM, respectively) but not MCF-7 cells (IC50=3600 nM). EKB-569 is also a potent inhibitor of EGF-induced phosphorylated EGF-R (pEGF-R) in A431 and NHEK cells (IC50=20-80 nM)[1].
A single oral dose of 10 mg/kg EKB-569 inhibits EGFR phosphorylation in A431 xenografts within 60 minutes. Twenty-four hours later, EGFR activity is still inhibited by over 50% by this single oral dose. The half-life of EKB-569 in mouse plasma is about 2 hours[1].

Reference

[1]. Torrance CJ, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med. 2000 Sep;6(9):1024-8.
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[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 Jan;3(1):21-7.
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