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

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

  • Bioorg Med Chem Lett. 2026 Mar 28:137:130642. doi: 10.1016/j.bmcl.2026.130642.
Michael J Williams 1,  Conor T Ronayne 2,  Tanner J Schumacher 1,  Kayla M Johnson 3,  Matthew D Wittmer 4,  Joseph L Johnson 5,  Grant W Anderson 6,  Venkatram R Mereddy 5
Affiliations

Affiliations

  • 1 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
  • 2 Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, United States. Electronic address: ronay013@d.umn.edu.
  • 3 Department of Biomedical Sciences, School of Medicine, University of Minnesota, Duluth, MN 55812, United States.
  • 4 Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
  • 5 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States; Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, United States.
  • 6 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, United States.
PMID: 41912098 DOI: 10.1016/j.bmcl.2026.130642
Abstract

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.

Keywords

ATF4; Integrated stress response; MetAP2; Nitroxoline; mTORC1.

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