Nilotinib(AMN-107)

Nilotinib(AMN-107) is a selective oral tyrosine kinase inhibitor that inhibits the autophosphorylation of native Bcr-Abl (WT p210) and mutant Bcr-Abl (E281K, E292K, F317L, M351T, and F486S) with IC₅₀ values of 20, 42, 31, 38, 29, and 41nM, respectively^[1]. Nilotinib inhibits lymphocyte-specific protein tyrosine kinase (LCK) with an IC₅₀ of 550nM^[2]. Nilotinib is an aminopyrimidine-based high-affinity ATP-competitive inhibitor^[3].

In vitro, treatment of CD8⁺ T cells with Nilotinib (4µM) for 0-48h significantly inhibited PHA/IL-2-stimulated cell proliferation, downregulated the expression of CD8⁺ T cell activation markers CD69 and CD25, and reduced the phosphorylation of ERK 1/2 and LCK proteins^[4]. Nilotinib (5µM) treatment of CD34⁺ cells from chronic myeloid leukemia (CML) patients for 16h inhibited CrkL phosphorylation but did not induce apoptosis^[5].

In vivo, oral treatment of gastrointestinal stromal tumor (GIST) mice with Nilotinib (40mg/kg/day) for 4 weeks inhibited tumor growth by 69.6%, 85.3% and 47.5% in GK1X, GK2X and GK3X xenograft lines, respectively^[6]. Oral treatment of leukemia mice with Nilotinib (75mg/kg/day) for 30 days significantly prolonged the survival of the mice, and visible lymphoma masses disappeared within six days of treatment, and the number of leukemia cells in the peripheral blood was significantly reduced^[7].

References:
[1] Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL[J]. British journal of cancer, 2006, 94(12): 1765-1769.
[2] Blake S J, Lyons A B, Hughes T P. Nilotinib inhibits the Src-family kinase LCK and T-cell function in vitro[J]. Journal of cellular and molecular medicine, 2009, 13(3): 599.
[3] Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib[J]. Drug design, development and therapy, 2009: 89-101.
[4] Chen J, Schmitt A, Chen B, et al. Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling[J]. Journal of cellular and molecular medicine, 2008, 12(5b): 2107-2118.
[5] Jørgensen 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[J]. Blood, 2007, 109(9): 4016-4019.
[6] Sako H, Fukuda K, Saikawa Y, et al. Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells[J]. PloS one, 2014, 9(9): e107613.
[7] Kaur P, Feldhahn N, Zhang B, et al. Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia[J]. Molecular cancer, 2007, 6: 1-11.

Nilotinib(AMN-107)（尼洛替尼）是一种选择性口服酪氨酸激酶抑制剂，可抑制天然Bcr-Abl（WT p210）和突变型Bcr-Abl（E281K、E292K、F317L、M351T和F486S）的自磷酸化，IC₅₀值分别为20、42、31、38、29和41nM^[1]。Nilotinib能够抑制淋巴细胞特异性蛋白酪氨酸激酶（LCK），IC₅₀为550nM^[2]。Nilotinib是一种基于氨基嘧啶的高亲和力ATP竞争性抑制剂^[3]。

在体外，Nilotinib（4µM）处理CD8⁺ T细胞0-48h，显著抑制了PHA/IL-2刺激的细胞增殖，下调了CD8⁺ T细胞激活标志物CD69和CD25的表达，降低了ERK 1/2和LCK蛋白的磷酸化^[4]。Nilotinib（5µM）处理来自慢性粒细胞白血病（CML）患者的CD34⁺ 细胞16h，抑制了CrkL磷酸化但不诱导细胞凋亡^[5]。

在体内，Nilotinib（40mg/kg/day）通过口服治疗胃肠道间质瘤（GIST）小鼠4周，在GK1X、GK2X和GK3X异种移植系中对肿瘤生长抑制率分别为69.6%、85.3%和47.5%^[6]。Nilotinib（75mg/kg/day）通过口服治疗白血病小鼠30天，显著延长了小鼠的存活时间，治疗六天内肉眼可见的淋巴瘤肿块消失，外周血中的白血病细胞数量显著减少^[7]。