华西口腔医学杂志 ›› 2021, Vol. 39 ›› Issue (5): 493-500.doi: 10.7518/hxkq.2021.05.001
• 专家论坛 • 下一篇
收稿日期:
2020-11-24
修回日期:
2021-07-17
出版日期:
2021-10-01
发布日期:
2021-10-11
通讯作者:
冯晓东
E-mail:xiaodongfeng@scu.edu.cn
作者简介:
冯晓东,研究员,博士,E-mail:基金资助:
Received:
2020-11-24
Revised:
2021-07-17
Online:
2021-10-01
Published:
2021-10-11
Contact:
Feng Xiaodong.
E-mail:xiaodongfeng@scu.edu.cn
Supported by:
摘要:
YAP/ TAZ在头颈肿瘤中普遍异常激活,且对肿瘤生长调控意义重大,故直接靶向YAP/TAZ在头颈部肿瘤治疗中具有极高的潜能。但是随着研究的深入,该策略的局限性也逐步体现,主要表现为两点:1)受限于当前技术水平,暂时还没有发展出安全特异的YAP/TAZ转录辅助激活抑制剂;2)YAP/TAZ调控正常细胞增殖和生存、维持组织成体干细胞的自我更新、参与器官发育、组织大小调节、组织再生等重要生理进程,直接靶向YAP/TAZ可能对这些重要的正常生理活动造成不良影响,存在较大的策略风险。值得注意的是,YAP/TAZ在头颈肿瘤中的异常分子变化比例有限,其异常激活主要源于上游异常分子事件。因此通过研究YAP/TAZ在头颈肿瘤中激活的上游异常分子事件及调控机制,或可为间接靶向YAP/TAZ治疗头颈部肿瘤提供广阔前景。
中图分类号:
冯晓东. 直接或间接靶向YAP/TAZ治疗头颈部肿瘤的策略选择[J]. 华西口腔医学杂志, 2021, 39(5): 493-500.
Feng Xiaodong.. Targeting-YAP/TAZ therapies for head and neck cancer, directly or indirectly?[J]. West China Journal of Stomatology, 2021, 39(5): 493-500.
表 1
直接靶向YAP/TAZ-TEAD的抑制剂及靶点
名称 | 靶点 | 活性 | 模型 | 文献/专利 |
---|---|---|---|---|
维替泊芬 | YAP-TEAD相互作用(机制并不完全清楚) | TEAD转录活性降低 | 葡萄膜黑色素瘤(体内、体外);视网膜母细胞瘤 | [ |
CA3 | 抑制方式和与YAP相互作用的机制仍然未知 | 调节YAP/TEAD转录活性并降低YAP表达 | 食管腺癌(体内、体外) | [ |
芴-肟化合物类似物 | 机制并不完全清楚 | 降低YAP报告基因的活性 | 无 | [ |
基于双芳基肼支架化合物 | YAP/TAZ-TEAD相互作用(机制并不完全清楚) | TEAD-GAL4激活试验中中度活性;高浓度下对间皮瘤细胞系的抗增殖活性 | 间皮瘤细胞系(体外) | [ |
小分子抑制剂 WO2017/053706 | TEAD核心的脂质囊 | 抑制靶基因表达和细胞增殖 | 肝细胞系 | [ |
氟灭酸 | TEAD核心的脂质囊 | TEAD报告基因活性和一些Hippo通路反应基因活性下降 | 乳腺癌细胞系 | [ |
氟灭酸衍生物/TED-347 | YAP/TAZ-TEAD相互作用 | YAP-TEAD相互作用,转录活性降低 | 胶质母细胞瘤细胞系 | [ |
环状YAP样肽 | 内源性YAP竞争 | TEAD-YAP结合被抑制,YAP-TEAD转录活性 | 无 | [ |
super-TDU | 与YAP直接竞争TEAD的结合,抑制YAP的活性 | TEAD-YAP结合被抑制 | 胃癌、结直肠癌、肺癌(体内、体外) | [ |
CPD3.1 | 破坏YAP-TEAD蛋白质-蛋白质相互作用 | 抑制TEAD活性 | HeLa体外 | [ |
Peptide 17/yap样多肽(17mer) | 破坏YAP-TEAD蛋白质-蛋白质相互作用 | YAP-TEAD转录活性降低 | 肝癌(体内外)、骨肉瘤(体外) | [ |
雷公藤红素 | 直接与YAP/TAZ TEAD相互作用并破坏其作用 | YAP/TEAD转录活性降低 | 肺癌、乳腺癌(体外) | [ |
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