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

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.

癌症免疫治疗（Cancer immunotherapy）已在多种癌症的临床治疗中实现了革命性进展。由于肿瘤免疫原性（immunogenicity）较低，仅有少数患者能从该治疗中获益。特异性微管抑制剂（microtubule inhibitors）可有效诱导免疫原性细胞死亡（immunogenic cell death），并提升肿瘤的免疫原性。研究人员基于天然产物鬼臼毒素（podophyllotoxin）和双叶素（diphyllin）设计并合成了一系列异喹啉衍生物（isoquinoline derivatives）。其中，化合物F10对四种人类癌细胞系展现出强劲的抗增殖活性（antiproliferation activity），经验证其通过抑制微管蛋白（tubulin）与液泡型ATP酶（V-ATPase）发挥抗增殖作用。进一步研究表明，F10除可诱导细胞凋亡（apoptosis）外，还能诱发免疫原性细胞死亡。与此同时，F10可在RM-1同源移植瘤模型（RM-1 homograft model）中抑制肿瘤生长，并增强T淋巴细胞（T lymphocyte）的浸润程度。上述结果表明，F10有望成为新一代微管类药物开发的极具潜力的先导化合物（lead compound）。