Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors,Journal of Medicinal Chemistry

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Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-10 , DOI: 10.1021/acs.jmedchem.2c01346
Shingpan Chan ₁ , Yunong Zhang ₁ , Jie Wang ₁ , Qiuchun Yu ₁ , Xia Peng ₂ , Jian Zou ₁ , Licheng Zhou ₃ , Li Tan ₁ , Yunxin Duan ₁ , Yang Zhou ₁ , Hoon Hur ₄ , Jing Ai ₂ , Zhen Wang ₃ , Xiaomei Ren ₃ , Zhang Zhang ₁ , Ke Ding _{1,

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Affiliation

The receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, 6li, potently inhibited AXL enzymatic activity with an IC₅₀ value of 1.6 nM, and tightly bound with AXL protein with a K_d value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited AXL signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-β1-induced epithelial–mesenchymal transition, and dose-dependently impeded cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast cancer 4T1 cells. Taken together, this study provides a new potent and selective AXL inhibitor for further anticancer drug discovery.

中文翻译：

发现 3-氨基吡唑衍生物作为新的有效和口服生物可利用的 AXL 抑制剂

受体酪氨酸激酶 AXL 是抗癌药物发现的有前途的目标。在此，我们描述了 3-氨基吡唑衍生物作为新型强效选择性 AXL 激酶抑制剂的发现。代表性化合物之一 6li 可有效抑制 AXL 酶活性，IC ₅₀值为 1.6 nM，并与 AXL 蛋白紧密结合，K _d值为 0.26 nM，而对大多数 403 野生型的抑制作用明显较弱评估的激酶。基于细胞的测定表明，化合物6li有效抑制 AXL 信号传导，抑制 Ba/F3-TEL-AXL 细胞增殖，逆转 TGF-β1 诱导的上皮-间质转化，并以剂量依赖性方式阻碍癌细胞迁移和侵袭。化合物6li还在大鼠中显示出合理的药代动力学特性，并且在高转移性小鼠乳腺癌 4T1 细胞的异种移植模型中表现出显着的体内抗肿瘤功效。综上所述，本研究为进一步发现抗癌药物提供了一种新的强效选择性 AXL 抑制剂。

更新日期：2022-11-10

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