Nitroxoline-O-protected derivatives inhibit MetAP2 and activate ATF4 through mTORC1 to inhibit cancer cell growth.

Reprogrammed cancer cell proliferation requires high levels of protein synthesis and concomitant folding and processing. N-terminal methionine amino peptidases (MetAP) are a class of enzymes that cleave the initiator methionine amino acids to allow for peptide maturation and co-translational processing. The protein MetAP2 is upregulated in cancer cells and has been explored as a potential anticancer target. Cellular perturbations that impinge on protein synthesis activate cellular stress pathways, including the integrated stress response and mTORC1. Nitroxoline, a MetAP2 inhibitor has been explored as an anticancer agent but is hampered by poor pharmacokinetic properties. Here, we synthesized O-substituted silyl and nonsilyl nitroxoline analogs to diversify the nitroxoline template. In vitro MetAP2 and cancer cell proliferation inhibition assays demonstrated that synthesized analogs retain potency when compared to the parent nitroxoline. Mechanistically, we showed that the lead compound 3 and nitroxoline activate ATF4 mediated stress responses through non-canonical mTORC1. These results further implicate MetAP2 protein processing in mTORC1 nutrient sensing pathways and provide novel synthetic analogs of nitroxoline.