Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides

Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes.