Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activity.
Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs containing phosphorylated serine and threonine residues. To create small molecules that inhibit such interactions, we developed methodology for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small molecule inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concentrations when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concentration-dependent manner that correlates well with its ability to inhibit cell growth. This methodology can be applied to target a variety of proteins containing phosphoserine and other phosphoamino acid binding domains.
Department of Medicinal Chemistry and Molecular Pharmacology and the Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Allison
A
Arrendale
Keunho
K
Kim
Jun Young
JY
Choi
Wei
W
Li
Robert L
RL
Geahlen
Richard F
RF
Borch
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry; D015394:Molecular Structure; D010768:Phosphoserine / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D008024:Ligands; D011355:Prodrugs; D010768:Phosphoserine