Lei Mengrong, Huang Hanxue, Li Jiayi, Zhang Jinlin, Yu Geng, Jin Xin, Liu Junyan, Kang Fenghua, Liu Zhaoqian
Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, PR China.
Bioorg Med Chem Lett. 2025 Aug 1;123:130240. doi: 10.1016/j.bmcl.2025.130240. Epub 2025 Apr 12.
A series of hybrids (8a-h and 11a-h) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound 8a was identified as the most active compound with IC value of 0.28 μM in H1299 cells, superior to TAE226 (IC = 2.28 μM). In addition, 8a was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, 8a exhibited potent kinase inhibitory activity of FAK (IC = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC.
设计并合成了一系列含有2,4-二苯基嘧啶支架和香豆素部分的杂合物（8a-h和11a-h），作为新型的粘着斑激酶（FAK）抑制剂用于干预非小细胞肺癌（NSCLC）。大多数化合物有效抑制了NSCLC细胞的增殖，化合物8a被确定为活性最高的化合物，在H1299细胞中的IC值为0.28 μM，优于TAE226（IC = 2.28 μM）。此外，还发现8a能抑制NSCLC细胞的侵袭和迁移。此外，8a对FAK表现出强大的激酶抑制活性（IC = 4.968 nM），对各种激酶家族具有相当的选择性，随后导致H1299细胞中的细胞周期停滞、诱导凋亡以及MMP-2和MMP-9表达剂量依赖性降低。此外，8a对小鼠相对安全，并且在小鼠中比TAE226更有效地抑制植入的NSCLC肿瘤的生长。因此，8a可能是治疗NSCLC的有前途的候选药物。
