Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.
Biol Pharm Bull. 2011;34(12):1774-80. doi: 10.1248/bpb.34.1774.
The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.
大多数生长因子受体由细胞外、跨膜和细胞质酪氨酸激酶（TK）结构域组成。受体酪氨酸激酶（RTK）的激活调节许多关键过程，包括细胞生长和存活。然而，已发现 RTK 在广泛的癌症中失调，并且与许多癌症的发生和进展相关。因此，RTK 已成为一个有吸引力的治疗靶标。有效阻断 RTK 信号的一种方法是使用小分子抑制剂抑制其催化活性。针对具有突变 c-Kit 的肿瘤的低分子量 TK 抑制剂（TKI），如伊马替尼，以及针对具有突变表皮生长因子受体（EGFR）的非小细胞肺癌的吉非替尼，已在日本获得批准上市。MET、成纤维细胞生长因子受体（FGFR）和胰岛素样生长因子-I 受体（IGF-IR）在晚期癌症中经常发生遗传改变。这些受体的 TKI 尚未上市，但许多抗癌药物候选物目前正在临床试验中。这些 TKI 中的大多数旨在与 TK 结构域内的 ATP 结合位点竞争 ATP。这篇综述将重点介绍针对 MET、FGFR 和 IGF-IR 的小分子 TKI，并讨论两种类型的药物的优缺点，即仅针对一个或几个靶点的药物和针对多个靶点的药物。以前，基于窄靶窗可能减少意外副作用的假设，针对特定靶激酶的靶向药物是根据假设搜索的，但最近已经开发出针对多个靶标的药物来克服对单一靶标药物的耐药性肿瘤。
