Abstract：
The tropomyosin receptor tyrosine kinases (TRKs) control the cell proliferation mainly in the nervous system and are encoded by NTRK genes. Fusion and mutation of NTRK genes were detected in various types of cancers. Many small molecules TRK inhibitors have been discovered during the last two decades and some of them have entered clinical trials. Moreover, two of these inhibitors; larotrectinib and entrectinib; were approved by FDA for the treatment of TRK-fusion positive solid tumors. However, mutation of TRK enzymes resulted in resistance to both drugs. Therefore, next generation TRK inhibitors were discovered to overcome the acquired drug resistance. Additionally, the off-target and on-target adverse effects on the brain initiated the need for selective TRK subtype inhibitors. Indeed, some molecules were recently reported as selective TRKA or TRKC inhibitors with minimal CNS side effects. The current review highlighted the efforts done during the last three years in the design and discovery of novel TRK inhibitors.
摘要：
原肌球蛋白受体酪氨酸激酶（TRKs）主要在神经系统中控制细胞增殖，并由NTRK基因编码。在各种类型的癌症中检测到NTRK基因的融合和突变。在过去的二十年中，已经发现了许多小分子TRK抑制剂，其中一些已经进入临床试验。此外，其中两种抑制剂拉罗列替尼和恩列替尼被FDA批准用于治疗TRK融合阳性实体瘤.然而,TRK酶的突变导致对两种药物的抗性。因此,发现下一代TRK抑制剂可以克服获得性耐药性。此外,对脑的脱靶和脱靶的不良反应引发了对选择性TRK亚型抑制剂的需要.的确,一些分子最近被报道为选择性TRKA或TRKC抑制剂,其CNS副作用最小.本综述强调了过去三年在设计和发现新型TRK抑制剂方面所做的努力。
