Nuti Elisa, Rosalia Lea, Cuffaro Doretta, Camodeca Caterina, Giacomelli Chiara, Da Pozzo Eleonora, Tuccinardi Tiziano, Costa Barbara, Antoni Claudia, Vera Laura, Ciccone Lidia, Orlandini Elisabetta, Nencetti Susanna, Dive Vincent, Martini Claudia, Stura Enrico A, Rossello Armando
Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy; CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France.
ACS Med Chem Lett. 2017 Feb 7;8(3):293-298. doi: 10.1021/acsmedchemlett.6b00446. eCollection 2017 Mar 9.
Protein homodimers play important roles in physiological and pathological processes, including cancer invasion and metastasis. Recently, MMP-9 natural homodimerization via the PEX domain has been correlated with high migration rates of aggressive cancer cells. Here we propose that bifunctional MMP-9 inhibitors designed to impair natural MMP-9 homodimerization promoted by PEX-PEX interactions might be an effective tool to fight cancer cell invasion. Elaborating a previously described dimeric hydroxamate inhibitor , new ligands were synthesized with different linker lengths and branch points. Evaluation of the modified bifunctional ligands by X-ray crystallography and biological assays showed that and could reduce invasion in three glioma cell lines expressing MMP-9 at different levels. To rationalize these results, we present a theoretical model of full-length MMP-9 in complex with . This pioneering study suggests that a new approach using MMP-9 selective bifunctional inhibitors might lead to an effective therapy to reduce cancer cell invasion.
蛋白质同源二聚体在生理和病理过程中发挥着重要作用，包括癌症侵袭和转移。最近，基质金属蛋白酶-9（MMP-9）通过PEX结构域的天然同源二聚化与侵袭性癌细胞的高迁移率相关。在此，我们提出，设计用于破坏由PEX-PEX相互作用促进的天然MMP-9同源二聚化的双功能MMP-9抑制剂可能是对抗癌细胞侵袭的有效工具。通过精心设计先前描述的二聚体异羟肟酸酯抑制剂，合成了具有不同连接子长度和分支点的新配体。通过X射线晶体学和生物学试验对修饰后的双功能配体进行评估，结果表明，[具体化合物1]和[具体化合物2]可以降低在不同水平表达MMP-9的三种胶质瘤细胞系中的侵袭能力。为合理解释这些结果，我们展示了全长MMP-9与[具体化合物]复合物的理论模型。这项开创性研究表明，使用MMP-9选择性双功能抑制剂的新方法可能会带来一种有效降低癌细胞侵袭的治疗方法。
