生物活性

• 靶点

  EGFR IC50:92nM

  HER2 IC50:59nM

• 描述Deregulated expression of receptors EGFR and HER2, two closely related members of the ErbB family of transmembrane receptor tyrosine kinases, has been implicated in the development and malignancy of numerous types of human cancers, making them become a potential target for therapy. Neratinib is a potent inhibitor of HER2 and EGFR with IC50 values of 59nM and 92nM (measured by an autophosphorylation assay using time-resolved fluorometry), respectively. Neratinib>10nM could inhibit autophosphorylation of HER2 in BT474 cells treated for 3h, and EGF-induced autophosphorylation of EGFR in A431. Cell viability assays showed that Neratinib could inhibit HER-2-overexpressing breast cancer cell lines, SK-Br-3 and BT474, with low IC50 values (2nM), as well as EGFR-overexpressed cell line with IC50 value of 81nM, but exhibited much less activation on EGFR- and HER-2-negative cell lines, MDA-MB-435 and SW620. For activation of HER2 can lead to activation of both MAPK pathway and the Akt signal transduction pathways, a test for Neratinib on this two pathway has been done. Neratinib at concentration>2nM caused decreased level of both p-MAPK and p-AKT in BT474 cells. Treatment with Neratinib at concentration>5nM for 12-16h also led to decrease of cyclin D1 and retinoblastoma (Rb), as well as increased p27 in BT474, suggesting the cell cycle block by Neratinib. Oral administration of Neratinib at dose ranging in 10-80mg/kg exhibited anti-tumor activity against various tumor models, including 3T3/neu cells, BT474, SK-OV-3, A431 and MCF-7 xenografts^[1].
• 作用机制Neratinib binds irreversibly to the ATP binding pocket of HER member receptor tyrosine kinases.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  3T3	-	Growth Inhibition Assay	-	IC50=700 ± 78 nM	15173008
  3T3/neu	-	Growth Inhibition Assay	-	IC50=3 ± 0.14 nM	15173008
  A431	-	Growth Inhibition Assay	-	IC50=81 ± 9 nM	15173008

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• 动物研究
  剂量	Rat[3] (p.o.): 5 mg/kg - 100 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[3] Dogs[3] Dose 10 mg/kg 2 mg/kg (male) Administration p.o. p.o. Cmax 1.44 μg/ml 35.1 μg/ml AUC0→t 15.6 ng·hr/ml 323 ng·hr/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02396108	Breast Cancer	Phase 1 Phase 2	Recruiting	March 2019	Singapore ... more >> National University Hospital Recruiting Singapore, Singapore, 119228 Contact: Soo Chin Lee    (65) 6779 5555 Collapse <<
  NCT03182634	Advanced Breast Cancer	Phase 2	Recruiting	November 2023	United Kingdom ... more >> Royal Marsden Hosital, Sutton Recruiting Surrey, England, United Kingdom, SM2 5PT Royal Bournemouth Hospital Recruiting Bournemouth, United Kingdom Addenbrooke's Hospital Recruiting Cambridge, United Kingdom Royal Devon and Exeter Hospital Recruiting Exeter, United Kingdom Beatson West of Scotland Cancer Centre Recruiting Glasgow, United Kingdom Royal Marsden Hospital Recruiting London, United Kingdom University College Hospital London Recruiting London, United Kingdom Christie Hospital Recruiting Manchester, United Kingdom Collapse <<
  NCT00366600	Healthy	Phase 1	Completed	-	United States, Washington ... more >> Northwest Kinetics Tacoma, Washington, United States, 98418 Collapse <<

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• 参考文献

• [1] Rabindran SK, Discafani CM, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004 Jun 1;64(11):3958-65.

  [2] Feldinger K, Kong A, et al. Profile of neratinib and its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press). 2015 Jun 9;7:147-62.

  [3] 208051Orig1s000