Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase-2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
Tomoki Takeuchi, Yusaku Nomura, Tomoko Tamita, Rie Nishikawa, Hiroyuki Kakinuma, Naoki Kojima, Kosuke Hitaka, Yunoshin Tamura, M. Kamitani, Masashi Mima, Akiko Nozoe, Masato Hayashi
Abstract
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule–peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]–Glu–Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1′ pocket-binding group. The introduction of (4 S )-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 ( 18 ) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition ( K i = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life ( t 1/2 = 265 min).