ChemicalBook CAS DataBase List 1398312-64-5

1398312-64-5

Name	2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-, ethanedioate (1:2), (2E)-
CAS	1398312-64-5
Molecular Formula	C26H27ClFN5O7
Molecular Weight	575.98
MOL File	1398312-64-5.mol

Hazard Information

Uses

Afatinib (BIBW 2992) oxalate is an orally active, potent and irreversible dual specificity inhibitor of ErbB family (EGFR and HER2), with IC50 values of 0.5 nM, 0.4 nM, 10 nM and 14 nM for EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2, respectively. Afatinib oxalate can be used for the research of esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC) and gastric cancer[1][2][3][4].

in vivo

Afatinib oxalate (0-20 mg/kg, Orally, daily for 25 days) shows dramatic tumor regression and downregulation of EGFR, HER2, HER3 and AKT phosphorylation^[1].
Afatinib oxalate (15 mg/kg, Orally, in a schedule of 5 days on plus 2 days off, for two weeks) strongly inhibits the growth of HKESC-2 tumor^[2].

Animal Model:	Athymic NMRI-nu/nu female mice (21–31 g, five to six-week-old, transgenic murine lung cancer model and xenograft models)^[1]
Dosage:	15 mg/kg, 20 mg/kg
Administration:	Orally, daily for 25 days
Result:	Resulted in dramatic tumor regression with a cumulative treated/control tumor volume ratio (T/C ratio) of 2% in a standard xenograft model of the epidermoid carcinoma cell line A431, and downregulation of EGFR and AKT phosphorylation. Induced regression of large tumors in this HER2-driven model, effectively controlled xenograft tumor formation by the NCIH1975 cell line, expressing EGFR L858R/T790M, with a T/C value of 12% for doses of 20 mg/kg. Induced more than 50% percent tumor reduction after a 4-week treatment period. Downregulated EGFR, HER2 and HER3 phosphorylation.

Animal Model:	Six weeks old female athymic nude mice (nu/nu) (16-20 g)^[2]
Dosage:	15 mg/kg
Administration:	Oral gavage in a schedule of 5 days on plus 2 days off, for two weeks
Result:	Strongly inhibited the growth of HKESC-2 tumor. Average tumor sizes of vehicle and treatment at end point are 348 ± 24 mm³ and 108 ± 36 mm³ respectively.

IC 50

EGFR^L858R: 0.4 nM (IC₅₀); EGFR^WT: 0.5 nM (IC₅₀); EGFR^L858R/T790M: 10 nM (IC₅₀); HER2: 14 nM (IC₅₀); HER3

References

[1] Li D, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008 Aug 7;27(34):4702-11. DOI:10.1038/onc.2008.109
[2] Wong CH, et al. Preclinical evaluation of afatinib (BIBW2992) in esophageal squamous cell carcinoma (ESCC). Am J Cancer Res. 2015 Nov 15;5(12):3588-99. PMID:26885448
[3] Wang XK, et al. Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo. Oncotarget. 2014 Dec 15;5(23):11971-85. DOI:10.18632/oncotarget.2647
[4] Yoshioka T, et al. Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer. Cancer Sci. 2018 Apr;109(4):1166-1176. DOI:10.1111/cas.13546

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