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：

发现新型异喹啉类似物作为双微管蛋白聚合/V-ATP酶抑制剂，具有免疫原性细胞死亡诱导作用

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较低，只有少数患者可以从中受益。特异性微管抑制剂可以有效诱导免疫原性细胞死亡，提高肿瘤的免疫原性。以天然产物鬼臼毒素和二茶碱为基础，设计合成了一系列异喹啉衍生物。其中， F10对四种人类癌细胞系表现出强大的抗增殖活性，并证实F10通过抑制微管蛋白和V-ATPase发挥抗增殖活性。进一步的研究表明， F10除了诱导细胞凋亡外，还能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，并增强 T 淋巴细胞浸润。这些结果表明F10可能是开发新一代微管药物的有前途的先导化合物。

更新日期：2024-02-09

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