Christensen James G, Zou Helen Y, Arango Maria E, Li Qiuhua, Lee Joseph H, McDonnell Scott R, Yamazaki Shinji, Alton Gordon R, Mroczkowski Barbara, Los Gerrit
Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, La Jolla, CA 92121, USA.
Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3314-22. doi: 10.1158/1535-7163.MCT-07-0365.
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 IC(50) 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 (IC(50) values, approximately 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 (IC(50) 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.
一种导致名为核磷蛋白-间变性淋巴瘤激酶（NPM-ALK）的致癌激酶融合蛋白表达的t(2;5)染色体易位与间变性大细胞淋巴瘤（ALCL）的发病机制有关。PF-2341066最近被鉴定为一种口服生物可利用的小分子抑制剂，可抑制c-Met激酶和NPM-ALK融合蛋白的催化活性。PF-2341066还能有效抑制Karpas299或SU-DHL-1 ALCL细胞中的NPM-ALK磷酸化（平均IC(50)值为24 nmol/L）。在生化和细胞筛选中，PF-2341066在超过120种不同激酶的药理学相关浓度下对c-Met和ALK具有选择性。PF-2341066能有效抑制细胞增殖，这与ALK阳性ALCL细胞中的G(1)-S期细胞周期阻滞和凋亡诱导有关（IC(50)值约为30 nmol/L），但对ALK阴性淋巴瘤细胞无效。使用末端脱氧核苷酸转移酶介导的缺口末端标记和膜联蛋白V染色证实了凋亡的诱导（IC(50)值为25 - 50 nmol/L）。对携带Karpas299 ALCL肿瘤异种移植物的严重联合免疫缺陷-米色小鼠口服PF-2341066，在初始化合物给药后15天内，100 mg/kg/d剂量下所有肿瘤完全消退，呈现剂量依赖性抗肿瘤疗效。在抗肿瘤反应与肿瘤组织中NPM-ALK磷酸化抑制和凋亡诱导之间观察到强烈的相关性。此外，在与NPM-ALK磷酸化和功能抑制相关的浓度或剂量水平下，观察到PF-2341066对关键的NPM-ALK信号转导介质的抑制作用，包括磷脂酶C-γ、信号转导和转录激活因子3、细胞外信号调节激酶和Akt。总体而言，这些数据说明了NPM-ALK抑制剂在治疗ALK阳性ALCL患者中的潜在临床应用价值。
