Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction,Journal of Medicinal Chemistry

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Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-09 , DOI: 10.1021/acs.jmedchem.3c02399
Jiafu Leng ₁ , Yongjun Zhao ₁ , Shifang Zhao ₁ , Shanshan Xie ₁ , Ping Sheng ₁ , Liqiao Zhu ₁ , Mengyu Zhang ₁ , Tingting Chen ₁ , Lingyi Kong ₁ , Yong Yin ₁

Affiliation

Cancer immunotherapy has revolutionized clinical advances in a variety of cancers. Due to the low immunogenicity of the tumor, only a few patients can benefit from it. Specific microtubule inhibitors can effectively induce immunogenic cell death and improve immunogenicity of the tumor. A series of isoquinoline derivatives based on the natural products podophyllotoxin and diphyllin were designed and synthesized. Among them, F10 showed robust antiproliferation activity against four human cancer cell lines, and it was verified that F10 exerted antiproliferative activity by inhibiting tubulin and V-ATPase. Further studies indicated that F10 is able to induce immunogenic cell death in addition to apoptosis. Meanwhile, F10 inhibited tumor growth in an RM-1 homograft model with enhanced T lymphocyte infiltration. These results suggest that F10 may be a promising lead compound for the development of a new generation of microtubule drugs.

中文翻译：

新型异喹啉类似物作为双微管蛋白聚合/V-ATP 酶抑制剂与免疫原性细胞死亡诱导的发现

癌症免疫疗法彻底改变了多种癌症的临床进展。由于肿瘤的免疫原性低，只有少数患者可以从中受益。特异性微管抑制剂可有效诱导免疫原性细胞死亡，提高肿瘤的免疫原性。设计合成了一系列基于天然产物鬼臼毒素和叶蛋白的异喹啉衍生物。其中，F10 对四种人癌细胞系表现出强大的抗增殖活性，并验证 F10 通过抑制微管蛋白和 V-ATP 酶发挥抗增殖活性。进一步的研究表明，F10 除了细胞凋亡外，还能够诱导免疫原性细胞死亡。同时，F10 抑制 RM-1 同种移植模型中的肿瘤生长，T 淋巴细胞浸润增强。这些结果表明，F10 可能是一种很有前途的先导化合物，可用于开发新一代微管药物。

更新日期：2024-02-09

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