Targeted Polypharmacology: Discovery of a Highly Potent Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-10/-13 Inhibitor

Matrix
metalloproteinases (MMPs) play a key role in many diseases
like cancer, atherosclerosis or arthritis. Interest in MMP inhibition
has been revitalized very recently as the knowledge on the underlying
network of biological pathways is steadily growing. On the basis of
this new insight into the relevance of MMP-10 and MMP-13 within the
MMP network and the ban of hydroxamate inhibitors from clinical development,
the discovery of non-hydroxamate multitarget drugs against specific
MMPs is of foremost interest. Here, we disclose the discovery of a
very potent and selective non-hydroxamate MMP-10/-13 inhibitor. The
high potency (IC50 of 31 nM [MMP-10] and 5 nM [MMP-13])
and selectivity over MMP-1, -2, -3, -7, -8, -9, -12, and -14 enable
this compound to decipher disease causing MMP networks and to generate
new treatment options through targeted polypharmacology.