Fangchinoline derivative LYY-34 suppresses TNBC by inhibiting BLM DNA helicase from unfolding of c-MYC promoter G-quadruplex DNA.

Excessive unfolding of G-quadruplex (G4) DNA in the c-MYC oncogene promoter leads to its overexpression and promotes cancer progression. Triple-negative breast cancer (TNBC) frequently exhibits c-MYC amplification. Bloom syndrome (BLM) DNA helicase can efficiently unwind c-MYC promoter G4 DNA. This study investigated the antitumor mechanism of the fangchinoline derivative LYY-34 on TNBC by targeting BLM DNA helicase-mediated unfolding of c-MYC promoter G4 DNA. We first demonstrated that LYY-34 inhibits the binding and unfolding activities of BLM DNA helicase on c-MYC promoter G4 DNA. Furthermore, we found that this inhibition primarily results from LYY-34 competitively binding to the 3'-DNA overhang of the c-MYC promoter G4 and directly interacting with BLM DNA helicase, thereby suppressing BLM DNA helicase activity, rather than stabilizing the G4 structure. Bioinformatics analysis combined with in vitro experiments showed that BLM DNA helicase modulates c-MYC expression. In addition, both in vitro and in vivo antiproliferation experiments demonstrated that LYY-34 significantly suppresses TNBC. Further studies revealed that this inhibitory effect is associated with its suppression of BLM DNA helicase and c-MYC expression. In summary, LYY-34 may serve as a potential therapeutic agent for TNBC by inhibiting the BLM DNA helicase /c-MYC axis.