FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways.
FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways.
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FAK PROTAC 通过破坏激酶依赖和独立途径抑制卵巢肿瘤生长和转移
DOI：
10.3389/fonc.2022.851065
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
局灶黏附激酶（FAK）在多种人类癌症中高度表达，是癌症治疗的靶点。由于FAK激酶抑制剂仅阻断FAK的激酶活性，因此在临床试验中效果不佳。FAK也在激酶不依赖的途径中作为支架蛋白起作用。为了有效靶向FAK，需要阻断FAK激酶依赖性和FAK非依赖性通路。因此，我们测试了用于卵巢癌治疗的新一代药物FAK PROTAC，它可以阻断激酶和支架活性。通过细胞增殖、迁移、侵袭等功能实验，验证了FAK PROTAC及其亲本激酶抑制剂VS-6063对卵巢癌细胞系的体外作用。我们还测试了原位卵巢癌小鼠模型的体内活性。此外，我们评估了FAK PROTAC是否破坏激酶依赖性和激酶非依赖性通路。我们证明FAK PROTAC在抑制细胞增殖、存活、迁移和侵袭方面比其亲本FAK激酶抑制剂VS-6063更有效。FAK PROTAC不仅抑制FAK激酶活性，而且通过破坏FAK与其相互作用蛋白ASAP1之间的相互作用抑制FAK支架功能。我们进一步发现FAK PROTAC能有效抑制卵巢肿瘤的生长和转移。综上所述，FAK PROTAC通过破坏FAK与ASAP1之间的相互作用抑制FAK激酶活性及其支架蛋白活性，在抑制卵巢肿瘤生长和转移方面非常有效。
Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis.
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影响因子：
3.7
作者：
Chen Z;Wang Y;Liu W;Zhao G;Lee S;Balogh A;Zou Y;Guo Y;Zhang Z;Gu W;Li C;Tigyi G;Yue J
通讯作者：
Yue J
影响因子：
16
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
通讯作者：
Llic, Dusko
影响因子：
4.7
作者：
Lee, So Myoung;Kang, Chung Hyo;Park, Chi Hoon
通讯作者：
Park, Chi Hoon
影响因子：
11.5
作者：
Ehlers, JP;Worley, L;Harbour, JW
通讯作者：
Harbour, JW
影响因子：
7.7
作者：
Diaz Osterman, Carlos J.;Ozmadenci, Duygu;Schlaepfer, David D.
通讯作者：
Schlaepfer, David D.