华东师范大学Xiong-wen Zhang等研究人员合作发现，一种新型FAK降解PROTAC分子同时具有抗肿瘤活性和高效的MDR逆转效应。2024年6月6日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

研究人员采用了PROTAC技术，在FAK（焦点粘附激酶）抑制剂IN10018的基础上设计了一种新型的靶向FAK的PROTAC分子F2。F2对4T1、MDA-MB-231、MDA-MB-468和MDA-MB-435细胞具有强效抑制活性，IC50值分别为0.73、1.09、5.84和3.05μM。另一方面，F2还能显著逆转HCT8/T、A549/T和MCF-7/ADR细胞的多药耐药性（MDR）。F2的这两种作用都强于FAK抑制剂IN10018。

据研究人员所知，F2是第一个报道的对化疗药物耐药性有逆转作用的FAK靶向PROTAC分子，其最高逆转倍数可达158倍。F2的抗肿瘤和MDR逆转作用可能是基于其对AKT（蛋白激酶B，PKB）和ERK（细胞外信号调节激酶）信号通路的抑制，以及对EMT（上皮-间质转化）的影响。此外，研究人员还发现F2可以降低HCT8/T细胞中P-gp的蛋白水平，从而从另一个角度逆转耐药性。这些研究结果将增强未来以FAK为靶点的研究信心，并鼓励进一步研究具有强大体内效应的PROTAC。

据悉，FAK广泛参与癌症的生长和耐药性的产生。因此，抑制FAK已成为一种有效的肿瘤治疗策略，既可作为一种单一疗法，也可与其他疗法联合使用。但目前的FAK抑制剂主要集中在其激酶活性上，忽略了FAK支架蛋白的潜在意义。

附：英文原文

Title: A novel FAK-degrading PROTAC molecule exhibited both anti-tumor activities and efficient MDR reversal effects

Author: Xu, Ming-shi, Gu, Xiao-fan, Li, Cong, Pan, Li-xuan, Zhu, Zi-xia, Fan, Meng, Zhao, Yun, Chen, Jian-fang, Liu, Xuan, Zhang, Xiong-wen

Issue&Volume: 2024-06-06

Abstract: FAK (focal adhesion kinase) is widely involved in cancer growth and drug resistance development. Thus, FAK inhibition has emerged as an effective strategy for tumor treatment both as a monotherapy or in combination with other treatments. But the current FAK inhibitors mainly concentrate on its kinase activity, overlooking the potential significance of FAK scaffold proteins. In this study we employed the PROTAC technology, and designed a novel PROTAC molecule F2 targeting FAK based on the FAK inhibitor IN10018. F2 exhibited potent inhibitory activities against 4T1, MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells with IC50 values of 0.73, 1.09, 5.84 and 3.05μM, respectively. On the other hand, F2 also remarkably reversed the multidrug resistance (MDR) in HCT8/T, A549/T and MCF-7/ADR cells. Both the effects of F2 were stronger than the FAK inhibitor IN10018. To our knowledge, F2 was the first reported FAK-targeted PROTAC molecule exhibiting reversing effects on chemotherapeutic drug resistance, and its highest reversal fold could reach 158 times. The anti-tumor and MDR-reversing effects of F2 might be based on its inhibition on AKT (protein kinase B, PKB) and ERK (extracellular signal-regulated kinase) signaling pathways, as well as its impact on EMT (epithelial-mesenchymal transition). Furthermore, we found that F2 could reduce the protein level of P-gp in HCT8/T cells, thereby contributing to reverse drug resistance from another perspective. Our results will boost confidence in future research focusing on targeting FAK and encourage further investigation of PROTAC with potent in vivo effects.

DOI: 10.1038/s41401-024-01312-w

Source: https://www.nature.com/articles/s41401-024-01312-w