Haluska Paul, Carboni Joan M, Loegering David A, Lee Francis Y, Wittman Mark, Saulnier Mark G, Frennesson David B, Kalli Kimberly R, Conover Cheryl A, Attar Ricardo M, Kaufmann Scott H, Gottardis Marco, Erlichman Charles
Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Cancer Res. 2006 Jan 1;66(1):362-71. doi: 10.1158/0008-5472.CAN-05-1107.
The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 micromol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.
胰岛素样生长因子受体（IGF-IR）和胰岛素受体在多种肿瘤类型中过度激活和/或过度表达，促进肿瘤发生、增殖、转移和耐药。在此，我们表明，作为IGF-IR抑制剂开发的新型小分子BMS-554417在体外抑制IGF-IR和胰岛素受体激酶活性及增殖，并在体内减小肿瘤异种移植瘤的大小。在一系列癌细胞系中，增殖的IC50范围为120 nmol/L（Colo205）至>8.5 μmol/L（OV202）。在MCF-7和OV202细胞中，抗增殖作用无需添加刺激性配体。BMS-554417处理通过细胞外信号相关激酶以及磷酸肌醇3激酶/Akt途径抑制IGF-IR和胰岛素受体信号传导，Ser473处Akt磷酸化降低证明了这一点。在抑制增殖的剂量下，该化合物还导致G0-G1期阻滞，并阻止细胞周期蛋白D1响应LR3 IGF-I在细胞核内积累。在Jurkat T细胞白血病细胞中，该药物通过线粒体途径引发凋亡性细胞死亡。BMS-554417口服具有生物利用度，并在体内显著抑制IGF1R-Sal肿瘤异种移植瘤的生长。BMS-554417是一类新型IGF-IR/胰岛素受体抑制剂的成员，因其在体外和体内的抗增殖和促凋亡活性而具有潜在临床应用价值。
