Discovery of Novel Allosteric Inhibitors of Deoxyhypusine Synthase

Deoxyhypusine
synthase (DHPS) utilizes spermidine and NAD as cofactors
to incorporate a hypusine modification into the eukaryotic translation
initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation,
which, in turn, plays a key role in regulating protein translation
of selected mRNA that are associated with the synthesis of oncoproteins,
thereby enhancing tumor cell proliferation. Therefore, inhibition
of DHPS is a promising therapeutic option for the treatment of cancer.
To discover novel lead compounds that target DHPS, we conducted synthetic
studies with a hit obtained via high-throughput screening. Optimization
of the ring structures of the amide compound (2) led
to bromobenzothiophene (11g) with potent inhibitory activity
against DHPS. X-ray crystallographic analysis of 11g complexed
with DHPS revealed a dramatic conformational change in DHPS, which
suggests the presence of a novel allosteric site. These findings provide
the basis for the development of novel therapy distinct from spermidine
mimetic inhibitors.