新型黏附斑激酶FAK抑制剂的设计、合成及抗肿瘤转移活性研究

Tumor invasion and metastasis remain principal causes for the resultant mortality of patients with cancer. The development of focal adhesion kinase (FAK) inhibitor has been considered as a promising strategy for the intervention of tumor metastasis. However, previous efforts to develop FAK inhibitor were mainly limited to kinase inhibitors, which lack of intervention on the kinase-independent signaling mediated by up-regulation of FAK expression, thus demonstrating poor therapeutic effect in clinical studies. A series of evidences suggest that nitric oxide (NO) or lysyloxidase-like 2 (LOXL-2) inhibitor with confirmed anti-metastatic activity can downregulate FAK expression. Thereby, the work of proposed project herein include: 1) modifying and optimization the typically structure of known FAK kinase inhibitors via introducing the active fragment of NO donor or LOXL-2 inhibitor into one molecule to offers a possibility to simultaneously block FAK’s kinase signaling and downregulate FAK expression，and ultimately improve the anti-tumor metastasis activity; 2) in vitro and in vivo anti-tumor metastasis activity evaluation; 3) possible mechanisms underlying the anti-tumor metastasis activity exhibited by the corresponding target molecules. The purpose of the project is to develop novel FAK inhibitor which can be valuable for the prevention and treatment of cancer metastasis.

肿瘤转移是造成癌症患者死亡的主要原因，开发黏附斑激酶（FAK）抑制剂已成为干预肿瘤转移的有效策略。然而，现有FAK抑制剂主要为可阻断FAK活性的激酶抑制剂，缺乏对FAK表达上调介导的非激酶依赖信号通路进行干预，在临床研究中治疗效果不佳。大量研究提示，一氧化氮（NO）及赖氨酰氧化酶-2（LOXL-2）抑制剂均与FAK关系极为密切，除本身具有较强的抗肿瘤转移活性外，二者均可抑制FAK表达。基于此，本项目拟对现有FAK激酶抑制剂的典型结构进行优化，引入NO供体或具LOXL-2抑制活性片段，使目标分子在保持有效FAK激酶抑制活性的同时，可释放NO或抑制LOXL-2，降低FAK表达，即通过抑制FAK激酶活性和表达以及NO释放或抑制LOXL-2协同干预肿瘤转移。随后，对目标化合物进行系统的体内外抗肿瘤/抗肿瘤转移活性评价及作用机制研究，为最终获得具有高效抑制肿瘤转移活性的新型FAK抑制剂奠定基础。

开发黏附斑激酶（FAK）抑制剂已成为干预肿瘤转移的有效策略。但现有FAK抑制剂缺乏对非激酶依赖途径的干预，且抗肿瘤转移活性有待进一步提高。本项目对具有FAK抑制剂靶位结合特征的含氮杂环母体结构进行优化，引入可作用于FAK非激酶途径或具有抗肿瘤转移活性的功能片段，设计合成了三类新型FAK抑制剂：第一类的NO供体型FAK抑制剂，目标分子一方面能够在保留原有的激酶抑制活性，另一方面还能够释放高浓度NO，以非激酶依赖途径干预FAK的下游信号通路，最终实现对FAK激酶活性和非激酶功能的完全阻断，活性优于研究最为广泛的FAK激酶抑制剂，TAE226，获得了可有效抑制转移性TNBC的苗头化合物；第二类的FAK/LOXL-2双重抑制剂同时备与FAK和LOXL-2靶向结合的结构特征，发挥协同抗肿瘤转移活性；第三类的靶向FAT域的FAK抑制剂，通过天然取代肉桂酸的引入，改善了目标分子与FAK的非激酶FAT域的结合，干预FAK非激酶依赖功能，发挥抗TNBC转移活性。此外，我们还在探索了NO供体型FAK抑制剂在炎症动物模型中的潜在治疗应用。本项目取得的成果为开发可作用于非激酶依赖途径的FAK抑制剂提供了新的思路，通过本项目的实施，发表SCI论文3篇，申请专利1项，培养硕士生3人。