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.

中文翻译：

---

发现芳氧基苯基-七肽杂合体作为治疗特发性肺纤维化的有效和选择性基质金属蛋白酶 2 抑制剂

基质金属蛋白酶 2 (MMP2) 是一种锌依赖性内肽酶，在细胞外基质蛋白的降解中起重要作用。MMP2被认为是治疗各种疾病如癌症、关节炎和纤维化的有吸引力的靶标。在这项研究中，我们通过将与锌离子和 S2-S5 口袋结合的肽与与 S1' 口袋结合的小分子杂交，开发了一类新型 MMP2 选择性抑制剂。基于 X 射线晶体学的结构修改表明，在 4 位引入 2,4-二氨基丁酸 (Dab) 通过与 Glu130 形成静电相互作用显着增强了 MMP2 的选择性。提高代谢和化学稳定性后，TP0556351（9) 被识别。它表现出有效的 MMP2 抑制活性 (IC ₅₀ = 0.20 nM) 和极高的选择性。它抑制了博莱霉素诱导的小鼠特发性肺纤维化模型中胶原蛋白的积累，证明了 MMP2 选择性抑制剂对纤维化的功效。