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

ABSTRACT: 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 valida

SUBMITTER: Schultz CR 

PROVIDER: S-EPMC11912471 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature