Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors

Schultz, Chad R.; Aleiwi, Bilal; Zhou, X. Edward; Suino-Powell, Kelly; Melcher, Karsten; Almeida, Nuno M. S.; Wilson, Angela K.; Ellsworth, Edmund L.; Bachmann, André S.

doi:10.1021/acs.jmedchem.4c03120

Title: Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors

Journal Article · Tue Mar 04 00:00:00 UTC 2025 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.4c03120 · OSTI ID:2526631

Schultz, Chad R. ^[1]; Aleiwi, Bilal ^[2]; Zhou, X. Edward ^[3]; Suino-Powell, Kelly ^[3];

^[3];

^[4];

^[4]; Ellsworth, Edmund L. ^[2];

^[1]

Michigan State University, East Lansing, MI (United States); International Center for Polyamine Disorders, Grand Rapids, MI (United States)
College of Human Medicine, East Lansing, MI (United States)
Van Andel Institute, Grand Rapids, MI (United States)
Michigan State University, East Lansing, MI (United States)

We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.

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Research Organization:: Michigan State University, East Lansing, MI (United States)

Sponsoring Organization:: USDOE; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2526631

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 68; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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