Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation

Protein tyrosine phosphatases (PTPs) contribute to a striking variety
of human diseases, yet they remain vexingly difficult to inhibit with
uncharged, cell-permeable molecules; no inhibitors of PTPs have been
approved for clinical use. This study uses a broad set of biophysical
analyses to evaluate the use of abietane-type diterpenoids, a biologically
active class of phytometabolites with largely nonpolar structures,
for the development of pharmaceutically relevant PTP inhibitors. Results
of nuclear magnetic resonance analyses, mutational studies, and molecular
dynamics simulations indicate that abietic acid can inhibit protein
tyrosine phosphatase 1B, a negative regulator of insulin signaling
and an elusive drug target, by binding to its active site in a non-substrate-like
manner that stabilizes the catalytically essential WPD loop in an
inactive conformation; detailed kinetic studies, in turn, show that
minor changes in the structures of abietane-type diterpenoids (e.g.,
the addition of hydrogens) can improve potency (i.e., lower IC50) by 7-fold. These findings elucidate a previously uncharacterized
mechanism of diterpenoid-mediated inhibition and suggest, more broadly,
that abietane-type diterpenoids are a promising source of structurally
diverseand, intriguingly, microbially synthesizablemolecules
on which to base the design of new PTP-inhibiting therapeutics.