Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China.
Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, PR China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, PR China.
Bioorg Med Chem. 2022 Jul 15;66:116809. doi: 10.1016/j.bmc.2022.116809. Epub 2022 May 11.
To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.
为了寻找新型黏着斑激酶（FAK）抑制剂以干预转移性三阴性乳腺癌（TNBC），我们设计、合成并对一系列来源于氯吡咯烷和肉桂酸类似物的杂合 7a-s 进行了生物评估。最活跃的化合物 7d 能够在体外强烈抑制 TNBC 细胞的增殖、侵袭和迁移。我们对 7d 进行了对接分析，以阐明其与 FAK 支架的黏着斑靶向（FAT）结构域可能的结合模式。进一步的机制研究表明，7d 能够破坏 FAK 的 Y925 自身磷酸化，减少黏着斑（FA）和应力纤维（SF）的形成，并诱导 TNBC 细胞凋亡。总之，7d 是一种新型 FAK 抑制剂，可通过结合 FAT 结构域抑制 FAK 的必需非激酶支架功能，可能值得进一步研究以干预 TNBC。
