Zhang Chao, Rao Yu
Changping Laboratory, Beijing 102206, China.
State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
ACS Med Chem Lett. 2025 May 7;16(6):907-910. doi: 10.1021/acsmedchemlett.5c00184. eCollection 2025 Jun 12.
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase with enzymatic and scaffolding functions, composed of a FERM domain, kinase domain, proline-rich regions, and a FAT domain. It interacts with over 50 proteins and plays a key role in cancer progression, metastasis, and recurrence. Although eight FAK inhibitors have entered clinical trials, they primarily block kinase activity and fail to disrupt scaffolding functions. PROTAC technology offers a novel strategy by degrading the entire FAK protein, eliminating both functions. Several FAK-targeting PROTACs have been developed with promising results. Given FAK's critical role in tumor malignancy, combination therapiessuch as dual-target degradation or inhibitor-degrader strategiesmay provide enhanced anticancer efficacy.
粘着斑激酶(FAK)是一种具有酶促和支架功能的非受体酪氨酸激酶,由一个FERM结构域、激酶结构域、富含脯氨酸的区域和一个FAT结构域组成。它与50多种蛋白质相互作用,在癌症进展、转移和复发中起关键作用。尽管有8种FAK抑制剂已进入临床试验,但它们主要阻断激酶活性,无法破坏支架功能。PROTAC技术提供了一种通过降解整个FAK蛋白来消除这两种功能的新策略。已经开发出几种靶向FAK的PROTAC,并取得了有前景的结果。鉴于FAK在肿瘤恶性肿瘤中的关键作用,联合治疗——如双靶点降解或抑制剂-降解剂策略——可能会提供增强的抗癌疗效。