Golubovskaya Vita M, Nyberg Carl, Zheng Min, Kweh Frederick, Magis Andrew, Ostrov David, Cance William G
Department of Surgery, UF Shands Cancer Center, Department of Pathology and Laboratory Medicine,University of Florida, Gainesville, Florida 32610-0245, USA.
J Med Chem. 2008 Dec 11;51(23):7405-16. doi: 10.1021/jm800483v.
Focal adhesion kinase (FAK) is a nonreceptor kinase that is overexpressed in many types of tumors. We developed a novel cancer-therapy approach, targeting the main autophosphorylation site of FAK, Y397, by computer modeling and screening of the National Cancer Institute (NCI) small molecule compounds database. More than 140,000 small molecule compounds were docked into the N-terminal domain of the FAK crystal structure in 100 different orientations that identified 35 compounds. One compound, 14 (1,2,4,5-benzenetetraamine tetrahydrochloride), significantly decreased viability in most of the cells to the levels equal to or higher than control FAK inhibitor 1a (2-[5-chloro-2-[2-methoxy-4-(4-morpholinyl)phenylamino]pyrimidin-4-ylamino]-N-methylbenzamide, TAE226) from Novartis, Inc. Compound 14 specifically and directly blocked phosphorylation of Y397-FAK in a dose- and time-dependent manner. It increased cell detachment and inhibited cell adhesion in a dose-dependent manner. Furthermore, 14 effectively caused breast tumor regression in vivo. Thus, targeting the Y397 site of FAK with 14 inhibitor can be effectively used in cancer therapy.
粘着斑激酶（FAK）是一种非受体激酶，在多种肿瘤类型中过表达。我们通过计算机建模和筛选美国国立癌症研究所（NCI）小分子化合物数据库，开发了一种新型癌症治疗方法，靶向FAK的主要自磷酸化位点Y397。超过140,000种小分子化合物以100种不同取向对接至FAK晶体结构的N端结构域，从而鉴定出35种化合物。其中一种化合物14（1,2,4,5-苯四胺四盐酸盐）显著降低了大多数细胞的活力，使其达到或高于诺华公司的对照FAK抑制剂1a（2-[5-氯-2-[2-甲氧基-4-(4-吗啉基)苯基氨基]嘧啶-4-基氨基]-N-甲基苯甲酰胺，TAE226）的水平。化合物14以剂量和时间依赖性方式特异性且直接地阻断Y397-FAK的磷酸化。它以剂量依赖性方式增加细胞脱离并抑制细胞粘附。此外，化合物14在体内有效地导致乳腺肿瘤消退。因此，用化合物14抑制剂靶向FAK的Y397位点可有效地用于癌症治疗。
