AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia
AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia
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DOI：
10.1158/1078-0432.ccr-04-2601
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发表时间：
2005-07-01
影响因子：
11.5
通讯作者：
Beran, M
中科院分区：
文献类型：
--
作者：
Golemovic, M;Verstovsek, S;Beran, M
费城染色体阳性慢性髓细胞性白血病（CML）患者对伊马替尼的耐药或不耐受促使开发更有效的Bcr-Abl抑制剂。AMN 107是一种新型的Bcr-Abl的ATP竞争性抑制剂，比较了AMN 107与伊马替尼对伊马替尼敏感（KBM 5和KBM 7）和伊马替尼耐药（KBM 5-ST 1571（R1.0）和KBM 7-ST 1571（R1.0））的作用。与伊马替尼的抗增殖活性相比，AMN 107在KBM 5中的效力高43倍。（IC 50为11.3与480.5 nmol/L），在KBM 7中的效力高60倍在KBM 5-ST 1571中，AMN 107和伊马替尼的IC 50分别为2，418.3和6，361.4 nmol/L（IC 50为4.3 vs 259.0 nmol/L）在KBM 7-ST 1571 R（1.0）细胞中分别为97.2和2497.3 nmol/L。AMN 107在所有细胞系中比伊马替尼更有效地抑制Bcr-Abl激酶的自磷酸化。它们在这些细胞系中对细胞周期进程和凋亡反应具有相似的作用。在携带KBM 5细胞的严重联合免疫缺陷小鼠中，与对照组相比，从白血病细胞移植后第20天开始并持续20天，AMN 107 10、20和30 mg/kg/d给药组的平均存活时间分别为144%、159%和182%。这些结果强烈支持AMN 107在CML患者中的临床疗效的研究。
Resistance to or intolerance of imatinib in patients with Philadelphia chromosome - positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-ST1571(R1.0) and KBM7-ST1571(R1.0)). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells, IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-ST1571(R1.0), and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-ST1571R(1.0) cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.