MMP-9-IN-1

MMP-9-IN-1 is a selective inhibitor of matrix metalloproteinase-9 (MMP-9)，it works by targeting the plasma ceruloplasmin (PEX) domain of MMP-9, with a Kd value of 2.1μM^[1]. MMPs consist of a pro-peptide sequence, a catalytic (CAT) metalloproteinase domain, a hinge region or linker peptide, and a hemopexin (PEX) domain, among which the PEX domain is particularly important^[2]. MMP-9 plays key roles in various physiological and pathological processes, including extracellular matrix remodeling, tissue repair, inflammatory responses, and tumor invasion and metastasis^[3]. Therefore, MMP-9-IN-1 is often used in related research areas such as cancer, inflammatory diseases, and neurodegenerative diseases^[4-6].

In vitro, treatment of HT-1080 and MDA-MB-435 cells with 10μM MMP-9-IN-1 for 9 days significantly inhibits cell proliferation, migration and invasion without affecting cell viability^[1]. Treatment of BMSCs with 10μM MMP-9-IN-1 for 72h significantly inhibited MMP-9 activity but no significant effect on the proliferation^[7].

In vivo, C57BL6/J mice were intraperitoneally injected with MMP-9-IN-1 three days after ovariectomy (2mg/kg twice a week, for 8 weeks), MMP-9-IN-1 increased osteogenic differentiation protein expression, histone acetylation, promoted citric acid and acetyl-CoA secretion in BMSCs and restored osteogenic matrix formation in osteoblasts^[7].

References:
[1] Dufour, A., Sampson, N. S., Li, J., Kuscu, C., Rizzo, R. C., Deleon, J. L., Zhi, J., Jaber, N., Liu, E., Zucker, S., & Cao, J. (2011). Small-molecule anticancer compounds selectively target the hemopexin domain of matrix metalloproteinase-9. Cancer research, 71(14), 4977–4988.
[2] Okusha, Y., Eguchi, T., Sogawa, C., Okui, T., Nakano, K., Okamoto, K., & Kozaki, K. I. (2018). The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells. Journal of cellular biochemistry, 119(9), 7363–7376.
[3] Farina, A. R., & Mackay, A. R. (2014). Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. Cancers, 6(1), 240–296.
[4] Das, S., Amin, S. A., & Jha, T. (2021). Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies. European journal of medicinal chemistry, 223, 113623.
[5] Rashid, Z. A., & Bardaweel, S. K. (2023). Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment. International journal of molecular sciences, 24(15), 12133.
[6] Alford, V. M., Kamath, A., Ren, X., Kumar, K., Gan, Q., Awwa, M., Tong, M., Seeliger, M. A., Cao, J., Ojima, I., & Sampson, N. S. (2017). Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions. ACS chemical biology, 12(11), 2788–2803.
[7] Da, W., Jiang, W., & Tao, L. (2024). ROS/MMP-9 mediated CS degradation in BMSC inhibits citric acid metabolism participating in the dual regulation of bone remodelling. Cell death discovery, 10(1), 77.

MMP-9-IN-1是基质金属蛋白酶-9（MMP-9）的特异性抑制剂。它通过选择性靶向MMP-9的血浆铜蓝蛋白（PEX）结构域发挥作用，Kd值为2.1μM^[1]。MMPs具有前肽序列、催化（CAT）金属蛋白酶结构域、铰链区或连接肽和血凝素（PEX）结构域，其中PEX结构域是非常重要的结构域之一^[2]。MMP-9在多种生理和病理过程中发挥重要作用，如细胞外基质重塑、组织修复、炎症反应以及肿瘤的侵袭和转移等^[3]。因此，MMP-9-IN-1常用于相关研究，如癌症、炎症性疾病、神经退行性疾病等^[4-6]。

在体外，10μM MMP-9-IN-1处理HT-1080和MDA-MB-435细胞9天可显著抑制细胞增殖、迁移和侵袭，但不影响细胞活力^[1]。10μM MMP-9-IN -1处理骨髓间充质干细胞72h，可显著抑制MMP-9活性，但对骨髓间充质干细胞增殖无显著影响^[7]。

在体内实验中，C57BL6/J小鼠在卵巢切除术三天后腹腔注射MMP-9-IN-1（2mg/kg，每周两次，持续8周），结果显示MMP-9-IN-1增加了骨髓间充质干细胞（BMSCs）中成骨分化蛋白的表达、组蛋白乙酰化，促进了柠檬酸和乙酰辅酶A的分泌，并恢复了成骨细胞中成骨基质的形成^[7]。