Discovery and Optimization of a Novel Series of Pyrazolopyrimidines as Spermine Oxidase Inhibitors

Spermine
oxidase (SMOX) is associated with pathological processes
in cancer initiation and progression, driving interest in the search
for SMOX inhibitors. Currently available inhibitors exhibit moderate
activity and limited selectivity toward other polyamine-metabolizing
enzymes such as polyamine oxidase (PAOX), underscoring the urgent
need for potent and selective inhibitors of SMOX. This study focuses
on the optimization of a series of pyrazolopyrimidines, leading to
the discovery of JNJ-9350 as a potent inhibitor of human SMOX (hSMOX)
with unprecedented selectivity over other polyamine enzymes such as
hPAOX. Importantly, JNJ-9350 displays remarkable intracellular target
engagement and inhibition in cellular assays, positioning JNJ-9350
as a suitable tool compound for cellular experiments to further validate
the potential of SMOX inhibitors as anticancer therapeutics.