Rational Design of Selective Organoruthenium Inhibitors of Protein Tyrosine Phosphatase 1B

Protein tyrosine phosphatases (PTPs) belong to a large
family of
important regulatory enzymes involved in vital mammalian signaling
pathways. Selective inhibitors of PTPs are highly valuable from a
therapeutic standpoint given their association with various pathological
conditions. One such target is PTP-1B which has previously been linked
to diabetes and cancer. However, developing a selective inhibitor
against PTP-1B has proven to be daunting because the enzyme shares
a high degree of structural homology with TC-PTP, an essential PTP
involved in modulating immune functions. To address this challenge,
a series of organoruthenium complexes was developed to bind at the
PTP substrate-binding site while simultaneously target the peripheral
structural space. By capitalizing on the potential difference in the
structural environment proximal to the active site between different
PTPs, selectivity toward PTP-1B over TC-PTP was improved, paving the
way for organoruthenium complexes as selective PTP-1B metalloinhibitors.