Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function

Polyamine biosynthesis is regulated
by ornithine decarboxylase
(ODC), which is transcriptionally activated by c-Myc. A large library
was screened to find molecules that potentiate the ODC inhibitor,
difluoromethylornithine (DFMO). Anthranilic acid derivatives were
identified as DFMO adjunct agents. Further studies identified the
far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and
a master controller of specific genes including c-Myc and p21. We
showed that 9 does not inhibit 3H-spermidine
uptake yet works synergistically with DFMO to limit cell growth in
the presence of exogenous spermidine. Compound 9 was
also shown to inhibit the KH4 FUBP1–FUSE interaction in a gel
shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA
and protein expression, increase p21 mRNA and protein expression,
and deplete intracellular polyamines. This promising hit opens the
door to new FUBP1 inhibitors with increased potency.