Discovery of Highly Potent and Selective Matrix Metalloproteinase-7 Inhibitors by Hybridizing the S1' Subsite Binder with Short Peptides.
Tabuse H, Abe-Sato K, Kanazawa H, Yashiro M, Tamura Y, Kamitani M, Hitaka K, Gunji E, Mitani A, Kojima N, Oka Y.
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 <b>1</b>, 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 <b>1</b> with short peptides. The initially designed compound <b>6</b>, which was a hybrid molecule between <b>1</b> 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 <b>18</b> with remarkable potency for MMP-7 and selectivity over other MMP subtypes.