Matrix
metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase
that plays important roles in the degradation of extracellular matrix
proteins. MMP2 is considered to be an attractive target for the treatment
of various diseases such as cancer, arthritis, and fibrosis. In this
study, we have developed a novel class of MMP2-selective inhibitors
by hybridizing the peptide that binds to a zinc ion and S2–S5
pockets with small molecules that bind to the S1′ pocket. Structural
modifications based on X-ray crystallography revealed that the introduction
of 2,4-diaminobutanoic acid (Dab) at position 4 dramatically enhanced
MMP2 selectivity by forming an electrostatic interaction with Glu130.
After improving the metabolic and chemical stability, TP0556351 (9) was identified. It exhibited potent MMP2 inhibitory activity
(IC50 = 0.20 nM) and extremely high selectivity. It suppressed
the accumulation of collagen in a bleomycin-induced idiopathic pulmonary
fibrosis model in mice, demonstrating the efficacy of MMP2-selective
inhibitors for fibrosis.
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 MMP2selective 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 (4S)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).
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