Laird A D, Vajkoczy P, Shawver L K, Thurnher A, Liang C, Mohammadi M, Schlessinger J, Ullrich A, Hubbard S R, Blake R A, Fong T A, Strawn L M, Sun L, Tang C, Hawtin R, Tang F, Shenoy N, Hirth K P, McMahon G
SUGEN, Inc., San Francisco, California 94080, USA.
Cancer Res. 2000 Aug 1;60(15):4152-60.
Vascular endothelial growth factor, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor beta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic domain of FGF receptor 1 substantiated the adenine mimetic properties of its oxindole core. Molecular modeling of SU6668 in the ATP binding pockets of the FIk-1/KDR and PDGF receptor kinases provided insight to explain the relative potency and selectivity of SU6668 for these receptors. In cellular systems, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis after stimulation of cells by appropriate ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. Furthermore, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model revealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xenografts. Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials.
血管内皮生长因子、成纤维细胞生长因子（FGF）和血小板衍生生长因子（PDGF）及其同源受体酪氨酸激酶与实体瘤相关的血管生成密切相关。通过合理药物设计结合传统筛选技术，我们发现了SU6668，一种这些受体的新型抑制剂。使用分离的Flk-1、FGF受体1和PDGF受体β激酶进行的生化动力学研究表明，SU6668对ATP具有竞争性抑制特性。SU6668在FGF受体1催化结构域的共结晶学研究证实了其氧化吲哚核心的腺嘌呤模拟特性。SU6668在FIk-1/KDR和PDGF受体激酶的ATP结合口袋中的分子建模为解释SU6668对这些受体的相对效力和选择性提供了见解。在细胞系统中，SU6668在适当配体刺激细胞后抑制受体酪氨酸磷酸化和有丝分裂。在无胸腺小鼠中口服或腹腔注射SU6668导致多种人类肿瘤异种移植瘤（起源于胶质瘤、黑色素瘤、肺癌、结肠癌、卵巢癌和表皮样癌）显著生长抑制。此外，在背皮褶腔模型中对C6胶质瘤异种移植瘤进行的活体多荧光视频显微镜检查显示，SU6668治疗可抑制肿瘤血管生成。最后，SU6668治疗可使已形成的大型人类肿瘤异种移植瘤显著消退。目前正在对癌症患者进行SU6668活性的I期临床试验研究。
