Norlichexanthone, a shunt product of Griseofulvin, disrupts spindle assembly checkpoint and nucleocytoplasmic transport by targeting TPR in the nuclear pore complex

초록

Griseofulvin, a known antifungal, exhibits anticancer activity by disrupting centrosome clustering; however, its molecular target remains elusive. Here we report that griseofulvin impairs the Spindle Assembly Checkpoint (SAC) by binding directly to Mad1 and BubR1, interrupting the Mad1-Mad2 interaction and inducing mitotic cell death via multipolar spindle formation. Through chemical re-investigation of halogen substrate promiscuity of griseofulvin biosynthesis, we discovered that the shunt product norlichexanthone demonstrates significantly higher cytotoxicity than griseofulvin. Unlike griseofulvin, norlichexanthone induces both mitotic multipolar spindles and interphase nuclear membrane abnormalities. We found that norlichexanthone directly binds TPR, a scaffold protein essential for Mad1-Mad2 assembly at the nuclear pore complex (NPC). This novel dual mechanism—disrupting SAC assembly and nucleocytoplasmic transport—renders norlichexanthone a superior cytotoxic agent. Our findings position norlichexanthone as a promising chemotherapeutic candidate that promotes cancer cell death by targeting TPR-mediated pathways across both interphase and mitosis.

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