Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Cell Cycle. 2012 Sep 1;11(17):3250-9. doi: 10.4161/cc.21611. Epub 2012 Aug 16.
FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.
黏着斑激酶（FAK）和胰岛素样生长因子受体-1（IGF-1R）直接相互作用，从而激活有利于癌细胞的关键信号通路。FAK 和 IGF-1R 功能的抑制已被证明可显著降低癌细胞的增殖，并增加对化疗和放疗的敏感性。作为人类黑色素瘤的一种新方法，我们评估了一种破坏 FAK 和 IGF-1R 蛋白相互作用的小分子化合物的效果。之前，我们通过虚拟筛选和功能测试，确定了一种针对已知 FAK-IGF-1R 蛋白相互作用位点的先导化合物（INT2-31）。我们研究了该化合物破坏 FAK-IGF-1R 蛋白相互作用、抑制下游信号、降低人黑色素瘤细胞增殖、改变细胞周期进程、诱导细胞凋亡和减少体内肿瘤生长的能力。INT2-31 通过阻止 IRS-1 的激活，在体外和体内黑色素瘤细胞和肿瘤异种移植物中阻断 FAK 和 IGF-1R 的相互作用，导致 IGF-1 刺激时 AKT 的磷酸化减少。结果，INT2-31 显著抑制细胞增殖和活力（范围 0.05-10 μM）。更重要的是，21 天内通过腹腔注射给予 15mg/kg 的 INT2-31 破坏了 FAK 和 IGF-1R 的相互作用，并有效降低了肿瘤 AKT 的磷酸化，导致体内黑色素瘤肿瘤的显著消退。我们的数据表明，FAK-IGF-1R 蛋白相互作用是一个重要的靶点，用新型小分子（INT2-31）破坏这种相互作用具有人类黑色素瘤的潜在抗肿瘤治疗效果。
