Neratinib is an irreversible tyrosine kinase inhibitor with IC50s of 59 nM and 92 nM for HER2 and EGFR, respectively.
Neratinib has inhibition of tyrosine kinase KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively. This compound is 14- and 24-fold less active compared with HER2. Furthermore, Neratinib displays no activity against other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, as well as the tyrosine kinase c-Met.
In 3T3 cells transfected with the HER2 (3T3/neu), Neratinib selectively inhibits the proliferation of 3T3 cells. At the same time, Neratinib inhibits SK-Br-3 and BT474 cell growth with IC50 values of 2-3 nM.
Neratinib also inhibits the proliferation of EGFR -dependent A431 cells with an IC50 of 81 nM. At the same time, It reduces HER2 receptor autophosphorylation in BT474 cells with an IC50 of 5 nM, and EGF-dependent phosphorylation of EGFR in A431 cells with IC50 of 3 nM.
What’s more, Blocking of HER-2 by Neratinib results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM. Neratinib inhibits the cyclin D1 expression and the phosphorylation of the Rb-susceptibility gene production in BT474 cells with IC50 of 9 nM. As a result, Neratinib leads to G1-S arrest and ultimately decreased cell proliferation.
In vivo, Neratinib significantly inhibits the growth of xenografts with high levels of HER-2 and EGFR.
Neratinib significantly inhibits the growth of 3T3/neu xenografts. AT the dosage of 20, 40, and 80 mg/kg/day, Neratinib results in the inhibition of 53%, 98%, and 98%, respectively.
Additionally, Neratinib inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at doses of 5, 10, and 40 mg/kg/day, respectively. Furthermore, Neratinib is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively.
However, Neratinib is less potent against EGFR -dependent A431 xenografts than HER-2-dependent tumors. It exhibits 32% and 44% inhibition at 5 and 20 mg/kg/day, respectively. However, Neratinib displays little activity against MCF-7 and MX-1 xenografts expressing low levels of HER-2 and EGFR. All above suggests that Neratinib has a selective activity for cells expressing HER-2 or EGFR.
In conclusion, Neratinib exhibits tyrosine kinase inhibition in vitro and in vivo.