Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
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DOI：
10.1158/1535-7163.mct-07-0365
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发表时间：
2007-12-01
影响因子：
5.7
通讯作者：
Los, Gerrit
中科院分区：
文献类型：
--
作者：
Christensen, James G.;Zou, Helen Y.;Los, Gerrit
t(2;5) 染色体易位导致称为核磷蛋白-间变性淋巴瘤激酶 (NPM-ALK) 的致癌激酶融合蛋白的表达，这与间变性大细胞淋巴瘤 (ALCL) 的发病机制有关。 PF-2341066 最近被确定为邮政信箱。 c-Met 激酶和 NPM-ALK 融合蛋白催化活性的生物可利用小分子抑制剂。 PF-2341066 还有效抑制 Karpas299 或 SU-DHL-1 ALCL 细胞中的 NPM-ALK 磷酸化（平均 IC50 值，24 nmol/L）。在生化和细胞筛选中，PF-2341066 在超过 120 种不同激酶的组中显示出对药理学相关浓度的 c-Met 和 ALK 具有选择性。 PF-2341066 有效抑制细胞增殖，与 G(1)-S 期细胞周期停滞和诱导 ALK 阳性 ALCL 细胞凋亡相关（IC50 值，类似于 30 nmol/L），但与 ALK 阴性淋巴瘤细胞无关。使用末端脱氧核糖核苷酸转移酶介导的切口末端标记和膜联蛋白V染色(IC50值，25-50nmol/L)证实细胞凋亡的诱导。邮政信箱对带有 Karpas299 ALCL 肿瘤异种移植物的严重联合免疫缺陷米色小鼠施用 PF-2341066 产生了剂量依赖性抗肿瘤功效，在初始化合物施用后 15 天内，100 mg/kg/d 剂量下所有肿瘤完全消退。观察到抗肿瘤反应与抑制肿瘤组织中 NPM-ALK 磷酸化和诱导细胞凋亡之间存在很强的相关性。此外，在浓度或剂量水平上观察到 PF-2341066 对关键 NPM-ALK 信号传导介质（包括磷脂酶 C-gamma、信号转导子和转录激活子 3、细胞外信号调节激酶和 Akt）的抑制作用，这与 NPM-ALK 磷酸化和功能的抑制相关。总的来说，这些数据说明了 NPM-ALK 抑制剂在治疗 ALK 阳性 ALCL 患者中的潜在临床效用。
A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of > 120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells IC50 values, similar to 30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase-mediated nick-end labeling and Annexin V staining IC50 values, 25-50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL.