Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer because of the difficulty in diagnosis and its resistance to chemotherapy. Focal adhesion kinase (FAK) is found overexpressed in PDAC, and targeting FAK has been proved to impede the progress of PDAC. However, most of FAK inhibitors were reported to bind with FAK in a DFG-in conformation, leading to a limited anti-tumor effect in clinical studies. Herein, to develop FAK inhibitors targeting the inactive DFG-out conformation, a series of large aromatic rings were selected to improve the interaction with Phe565 of the DFG motif. Compound 26 was designed to effectively inhibit FAK and the proliferation of PANC-1 cells with IC₅₀ of 50.94 nM and 0.15 μM, respectively. Besides, compound 26 was proved to strongly suppress the proliferation, colony formation, migration, and invasion in FAK-overexpressing PDAC cells. This inhibitor was confirmed to induce the apoptosis and G2/M arrest in PANC-1 cells through the suppression of FAK/PI3K/Akt signal pathway. Meanwhile, compound 26 was found to simultaneously inhibit FAK with DFG-out conformation and JAK3/Aurora B (IC₅₀ of 9.99 nM and 0.49 nM, respectively). In vivo, compound 26 effectively inhibited the tumorigenesis and metastasis of PDAC with desirable biosafety. Overall, these results suggested that compound 26 was a promising candidate for the treatment of PDAC.

中文翻译：

---

发现一种靶向具有 DFG-out 状态和 JAK/Aurora 激酶的 FAK 的胰腺导管腺癌强效抗癌剂


胰腺导管腺癌 （PDAC） 是一种临床上具有挑战性的癌症，因为它难以诊断并且对化疗具有耐药性。发现黏着斑激酶 （FAK） 在 PDAC 中过表达，靶向 FAK 已被证明会阻碍 PDAC 的进展。然而，据报道，大多数 FAK 抑制剂以 DFG-in 构象与 FAK 结合，导致临床研究中抗肿瘤作用有限。在此，为了开发靶向失活 DFG-out 构象的 FAK 抑制剂，选择了一系列大的芳香环以改善与 DFG 基序的 Phe565 的相互作用。化合物 26 旨在有效抑制 FAK 和 PANC-1 细胞的增殖，IC₅₀ 分别为 50.94 nM 和 0.15 μM。此外，化合物 26 被证明强烈抑制 FAK 过表达 PDAC 细胞的增殖、集落形成、迁移和侵袭。该抑制剂被证实通过抑制 FAK/PI3K/Akt 信号通路诱导 PANC-1 细胞凋亡和 G2/M 阻滞。同时，发现化合物 26 同时抑制具有 DFG-out 构象和 JAK3/Aurora B 的 FAK （IC₅₀ 分别为 9.99 nM 和 0.49 nM）。在体内，化合物 26 有效抑制了 PDAC 的肿瘤发生和转移，具有理想的生物安全性。总体而言，这些结果表明化合物 26 是治疗 PDAC 的有前途的候选药物。