A Bcr-Abl inhibitor
Nilotinib is a selective, oral inhibitor of tyrosine kinase with IC50 values of 20, 42, 31, 38, 29 and 41 nM for the autophosphorylation of native BCR-ABL (WT p210) and mutant BCR-ABL (E281K, E292K, F317L, M351T and F486S), respectively [1].
Nilotinib was designed based on the structure of imatinib and showed the superiority over imatinib in newly diagnosed or imatinib-resistant chronic myelogenous leukemia (CML). It was more potent than imatinib to wild-type BCR-ABL in a wide range of CML-derived and transfected cell lines. Nilotinib was also efficacious in gastrointestinal stromal tumors. Nilotinib showed inhibition activities in KIT mutant cells, including KITV560del, KITK642E and KITV560G (IC50 value of 108 nM). It also was effect to double mutations of KIT, such as KITV560del/V654A, KITV559D/D820Y, KITV560del/V654A (IC50: 192 nM) and KITV559D/D820Y (IC50: 297 nM). Besides that, Nilotinib exerted selective inhibition of PDGFRα and PDGFRβ. It suppressed cell proliferation with IC50 value of 0.54 nM in EOL-1 cells with constitutive activation of FIP1L1-PDGFRα [1, 2].
参考文献:
[1] Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. British Journal of Cancer, 2006, 94(12): 1765-1769.
[2] Blay J Y, Von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor//Seminars in oncology. WB Saunders, 2011, 38: S3-S9.
| Cell experiment: [1] | |
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Cell lines |
CD34+ cells from individual patients with CML |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
5 μM, 16 hours |
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Applications |
After 16 hours in culture with nilotinib, long enough for inhibition of CrkL phosphorylation but not for induction of apoptosis, the total CD34+ cell samples studied exhibited only partial and variable inhibition (range, 49% to 0% inhibition) of CrkL phosphorylation. |
| Animal experiment: [2] | |
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Animal models |
C57Bl/6J mice injected with 8093 lymphoma cells |
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Dosage form |
Oral administration, 75 mg/kg, daily |
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Applications |
Vehicle treated mice became moribund within 3 weeks of the transplantation. They showed clear symptoms of ALL. Nilotinib-treated mice lived statistically significantly longer as compared with the vehicle-treated mice. This result clearly indicated that nilotinib was very effective in inhibiting the proliferation of the leukemic cells in vivo. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] J?rgensen H G, Allan E K, Jordanides N E, et al. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood, 2007, 109(9): 4016-4019. [2] Kaur P, Feldhahn N, Zhang B, et al. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia. Mol Cancer, 2007, 6(10): 67-77. | |
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