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© 2021 American Chemical Society.As c–MYC is one of the central players in triple–negative breast cancer (TNBC) oncogenesis, inhibiting c–MYC expression would be an effective anticancer strategy. Transcription–induced negative supercoiling is crucial in the regulation of c–MYC transcription, which facilitates the formation of a G4 structure in NHE III1 that can silence the transcription. However, topoisomerase 1 (Topo1) can dissipate this negative supercoiling, leading to continuous activation of c–MYC transcription. Thus, dual ligands targeting both Topo1 and c–MYC G4 appear to be significant in cancer therapy. In this study, a series of new dibenzoquinoxaline derivatives were designed, synthesized, and evaluated for both Topo1 and c–MYC inhibition. Among them, 5 was identified as the most promising dual ligand, which could effectively inhibit Topo1 activity and strongly stabilize c–MYC G4, thereby inhibiting cancer cell growth. Accordingly, this work suggests that this dual–targeting strategy may be effective in cancer therapy.
