Neratinib Inhibitor CAS No. 698387-09-6

Cat. No.	Name	Size	Price
KI0084	Neratinib	5 mg	$200
	Neratinib	25 mg	$700
	Neratinib	100 mg	$2032

Chemical Characteristic

Product Name	Neratinib
Synonyms	HKI-272
CAS No.	698387-09-6
Molecular Weight	557.04
Formula	C₃₀H₂₉ClN₆O₃
Chemical Name	(E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide
Smiles	C(=O)(/C=C/CN(C)C)Nc1cc2c(c(cnc2cc1OCC)C#N)Nc1cc(c(cc1)OCc1ccccn1)Cl
Chemical Structure
Documents	HPLC MS COA

Biological activities

Neratinib is a dual inhibitor of the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) kinases. The IC50 of neratinib is 92, 59 and 19 nM against EGFR, HER-2 and HER-4, respectively. Neratinib reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. Neratinib represses the proliferation of a mouse fibroblast cell line (3T3) transfected with the HER-2 oncogene (3T3/neu) by 50% (IC50) at 3 nM. Neratinib also inhibits two other HER-2-overexpressing breast cancer cell lines, SK-Br-3 and BT474 with an IC50 of 2 nM but is much less active on MDA-MB-435 and SW620 (a breast and a colon cancer cell line, respectively) that are EGFR- and HER-2-negative. Neratinib inhibits proliferation of the epidermal carcinoma cell line, A431, which overexpresses EGFR with an IC50 of 81 nM. HKI-272 decreased ligand-independent receptor phosphorylation by 50% (IC50) at 5 nM in BT474 cells. ^[1] Treatment of both H-1781 and Calu-3 cells with neratinib leads to inhibition of receptor phosphorylation and inhibition of the phosphoinositide 3 (PI3)-kinase and mitogen-activated protein (MAP)-kinase pathways at nanomolar concentrations.^[2] Neratinib remarkably enhances the sensitivity of ATP-binding cassette B1 (ABCB1)-overexpressing cells to ABCB1 substrates. Neratinib increases doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. ^[3] Neratinib reduces tumor growth in a dose-dependent manner when administered orally between 20 mg/kg/day (53% inhibition, day 21) and 80 mg/kg/day. In another test, neratinib shows antitumor effects between 10 mg/kg/day (34% inhibition, day 14) and 40 mg/kg/day (98% inhibition).^[1] Neratinib augments the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice.^[3]

Protocols

Neratinib is prepared as 10 mg/mL stocks in DMSO and diluted in 25 mM HEPES (pH 7.5; 0.002 ng/mL??0 µg/mL). ^[1]

References

[1] Rabindran SK, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004, 64(11): 3958-3965. [2] Minami Y, et al. The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene. 2007, 26(34): 5023-5027. [3] Zhao XQ, et al. Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. Mol Pharmacol. 2012, 82(1): 47-58.

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