5 research outputs found
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
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 (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 (Ki = 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 (t1/2 = 265 min)
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
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 (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 (Ki = 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 (t1/2 = 265 min)
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
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 (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 (Ki = 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 (t1/2 = 265 min)
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
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 (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 (Ki = 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 (t1/2 = 265 min)
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
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 (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 (Ki = 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 (t1/2 = 265 min)