药学学报, 2020, 55(5): 821-831
引用本文:
周晓菲, 李睿, 姚红娟, 李亮. ACK1小分子抑制剂的研究进展[J]. 药学学报, 2020, 55(5): 821-831.
ZHOU Xiao-fei, LI Rui, YAO Hong-juan, LI Liang. Advances in small molecule inhibitors of ACK1[J]. Acta Pharmaceutica Sinica, 2020, 55(5): 821-831.

ACK1小分子抑制剂的研究进展
周晓菲, 李睿, 姚红娟, 李亮
中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
摘要:
ACK1/TNK2(活化的Cdc42相关激酶)是一种非受体酪氨酸激酶,最初通过与GTP结合的小GTP酶Cdc42结合而被鉴定。它在人体中广泛表达,被EGF、PDGF、TGF-β等多种细胞外生长因子激活。激活的ACK1通过与下游效应子相互作用并使其磷酸化来介导信号级联反应。近年来对ACK1生物学功能及其参与癌症的研究多有报道,在肺癌、卵巢癌和前列腺癌等多种癌症中均发现ACK1的基因扩增和过表达,并与不良预后和转移表型相关,表明ACK1是癌症治疗的潜在靶点。因此,以ACK1为靶点研发高效选择性的小分子抑制剂可为癌症治疗提供潜在的候选药物。本综述简略描述了ACK1的激活方式以及在癌症中作用,介绍了靶向ACK1小分子抑制剂的最新研究进展,并展望和讨论了临床前研究中有应用前景的新型ACK1抑制剂。
关键词:   
Advances in small molecule inhibitors of ACK1
ZHOU Xiao-fei, LI Rui, YAO Hong-juan, LI Liang
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
ACK1 (activated Cdc42-associated kinase) is a non-receptor tyrosine kinase, originally identified by its binding to the GTP-binding small GTPase Cdc42. It is widely expressed in human tissues and activated by various extracellular growth factors such as EGF, PDGF and TGF-β. The activated ACK1 mediates the signaling cascade by interacting with downstream effectors followed by their phosphorylation. In recent years, researchers have investigated the biological functions of ACK1 and its roles in cancer research. The gene amplification and overexpression of ACK1 is associated with a poor prognosis and metastasis in a variety of cancers including lung, ovarian and prostate cancers. Therefore, the development of small molecule inhibitors of ACK1 provides promising opportunities for cancer-targeted therapy. In this review, we briefly describe recent advances in understanding the activation and biological function of ACK1 and introduce its novel inhibitors with potential therapeutic activities in preclinical studies.
Key words:   
收稿日期: 2019-10-22
DOI: 10.16438/j.0513-4870.2019-0831
基金项目: 国家自然科学基金资助项目(81302728,81472787,81773671,81828010);CAMS医学创新基金资助项目(2016-I2M-3-013);中国药物创新重大项目(2018ZX09711001-007).
通讯作者: 李亮,Tel:86-10-83166673,E-mail:liliang@imb.pumc.edu.cn
Email: liliang@imb.pumc.edu.cn
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