新型 FAK 抑制剂的设计、合成与生物评价，其对 IR 的选择性优于 TAE226。
Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226.
机构信息
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.
Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu, Sichuan 610096, China.
出版信息
Bioorg Chem. 2022 Jul;124:105790. doi: 10.1016/j.bioorg.2022.105790. Epub 2022 Apr 6.
In this study, 28 novel focal adhesion kinase (FAK) inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 18b displayed good inhibition of FAK (IC = 45 nM) with at least 22 fold of selectivity over insulin receptor (IR, IC > 1000 nM) and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC values of 0.27, 0.19 and 0.26 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 18b also inhibited the clone formation and migration of HCT-116 cells, tube formation of HUVECs, and stimulated cell cycle arrest in the G/M phase, inducing apoptosis by promoting ROS production. The FAK-Src-ERK signaling pathway was inhibited by 18b in a dose-dependent manner. Moreover, 18b showed adequate oral bioavailability of 16.37% and 75.90% tumor growth inhibition in the HCT116 xenograft model was observed. These results indicate that 18b is a promising selective inhibitor of FAK.
在这项研究中，基于 FAK 抑制剂 TAE226 设计并合成了 28 种新型粘着斑激酶（FAK）抑制剂。化合物 18b 对 FAK 具有良好的抑制作用（IC = 45 nM），对胰岛素受体（IR）的选择性至少为 22 倍（IC > 1000 nM），并对 Hela、HCT116 和 MDA-MB-231 细胞系表现出强大的抗癌活性，IC 值分别为 0.27、0.19 和 0.26 μM，而 TAE226 的 IC 值分别为 2.68、0.64 和 4.19 μM。18b 还抑制了 HCT-116 细胞的克隆形成和迁移、HUVECs 的管形成，并通过促进 ROS 产生来刺激细胞周期停滞在 G/M 期，诱导细胞凋亡。FAK-Src-ERK 信号通路被 18b 以剂量依赖性方式抑制。此外，18b 在 HCT116 异种移植模型中显示出 16.37%的良好口服生物利用度和 75.90%的肿瘤生长抑制作用。这些结果表明，18b 是一种有前途的 FAK 选择性抑制剂。
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