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.