Nilotinib

A potent, selective, orally available inhibitor of both native and mutant Bcr-Abl with IC50 of 20-80 nM; inhibits proliferation of Ba/F3 cells expressing G250E, E255K (V), F317L, M351T, F486S, M244V, L248R, Q252H, Y253H, E255K, E279K, E282D, V289S, and L348M Bcr-Abl mutants at <1 uM; also inhibits activated forms of PDGFR and c-Kit with IC50 of 30-200 nM; prolongs survival of mice with leukemia due to imatinib-resistant mutants of Bcr-Abl.Blood Cancer Approved (In Vitro) :Nilotinib (AMN107), selective Abl inhibitor, is designed to interact with the ATP-binding site of BCR-ABL with a higher affinity than imatinib while being significantly more potent compared with imatinib (IC50<30 nM), also maintains activity against most of the BCR-ABL point mutants that confer Imatinib resistance.Nilotinib demonstrates significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines which parent cell lines GK1C and GK3C shows imatinib sensitivity with IC50 of 4.59±0.97 μM and 11.15±1.48 μM, respectively, imatinib-resistant cell lines GK1C-IR and GK3C-IR shows Imatinib resistance with IC50 values of 11.74±0.17 μM (P<0.001) and 41.37±1.07 μM (P<0.001), respectively. (In Vivo) :Nilotinib (oral gavage, 40 mg/kg, daily, 4 weeks) shows equivalent or higher antitumor effects in BALB/cSLc-nu/nu mice with GIST xenograft.Nilotinib has a significant healing effect on the macroscopic and microscopic pathologic scores and ensures considerable mucosal healing in the indomethacin-induced enterocolitis rat model while decreases the PDGFR α and β levels and apoptotic scores in the colon.