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.