Erlotinib Hydrochloride Inhibitor CAS No. 183319-69-9

Product Name	Erlotinib Hydrochloride
Synonyms	Tarceva, CP 358774, NSC 718781, OSI 774, R 1415
CAS No.	183319-69-9
Molecular Weight	429.9
Formula	C₂₂H₂₃N₃O₄.HCl
Chemical Name	N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride
Smiles	N(c1ncnc2c1cc(c(c2)OCCOC)OCCOC)c1cc(ccc1)C#C Cl
Chemical Structure

Biological activities

Erlotinib is a selective, orally available small-molecule inhibitor of the HER1/EGFR tyrosine kinase domain, used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. The growth inhibitory effect of erlotinib is investigated in a panel of 42 NSCLC-derived cell lines under low serum tissue culture conditions with added EGFR ligand (TGF-α, 3 nM) to specifically activate EGFR. Using the Celltiter-Glo luminescent cell viability assay, NSCLC cell lines exhibit nearly a 2-log range in erlotinib IC50 (0.3 to??0 μM). Furthermore, KRAS mutations are identified in 31% of the NSCLC cell lines, which, interestingly, cluster primarily in cell lines of intermediate sensitivity (2-8 μM IC50) to erlotinib.^[1] The apparent Ki values for wild-type EGFR, the L858R and Del (746-750) mutants EGFR are 17.5, 6.3 and 3.3 nM, respectively. Besides, erlotinib inhibits TGFα-induced cellular proliferation with an IC50 of 12.9 nM for the NR6-EGFR Del (746-752) cell line, 40.5 nM for the NR6-EGFR L858R cell line, and 50.4 nM for the NR6-EGFR cell line.^[2] Erlotinib 20 and 100 mg/kg is given by gavage to female nu/nu athymic mice. The mice given 100 mg/kg have high systemic exposures to erlotinib, with an AUC_{last value of approximately 196 000 h.ng/mL and the AUC_{last following 20 mg/kg is 33 500 h.ng/mL. In the H460a NSCLC xenograft (day 28 post-tumor implantation), erlotinib, as a mono-therapy, has significant dose-dependent efficacy. In the 6.25 mg/kg , 12.5 mg/kg, 25 mg/kg and 100 mg/kg group there are growth inhibition of 28%, 36%, 46% and 61% (versus vehicle control)., respectively.^[3] When administered orally (by gavage) or parenterally (i.p.), erlotinib consistently produces significant, dose-related inhibition of HN5 EGFR tyrosine phosphorylation 1 hour after dosing the HN5 tumor xenografts. Furthermore, erlotinib produces dose-related inhibition of the s.c. growth of the human HN5 with an effective dosage for 50% inhibition (AED_{50) of 7 mg/kg/day p.o and 100% tumor growth inhibition of 12.5 mg/kg/day p.o.^[4]}}}

References

[1] Yauch RL, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 2005, 11(24 Pt 1):8686-8698. [2] Carey KD, et al. Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. Cancer Res. 2006, 66(16):8163-8171. [3] Higgins B, et al. Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs. 2004, 15(5):503-512. [4] Pollack VA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther. 1999 , 291(2):739-748.

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