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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 ( IF 4 ) Pub Date : 2017-10-10 00:00:00 , DOI: 10.1021/acschembio.7b00758
Vincent M. Alford 1, 2 , Anushree Kamath 3 , Xiaodong Ren 3 , Kunal Kumar 3 , Qianwen Gan 3 , Monaf Awwa 3 , Michael Tong 1 , Markus A. Seeliger 1, 4 , Jian Cao 2 , Iwao Ojima 3, 4 , Nicole S. Sampson 3, 4
Affiliation  

A lack of target specificity has greatly hindered the success of inhibitor development against matrix metalloproteinases (MMPs) for the treatment of various cancers. The MMP catalytic domains are highly conserved, whereas the hemopexin-like domains of MMPs are unique to each family member. The hemopexin-like domain of MMP-9 enhances cancer cell migration through self-interaction and heterointeractions with cell surface proteins including CD44 and α4β1 integrin. These interactions activate EGFR-MAP kinase dependent signaling that leads to cell migration. In this work, we generated a library of compounds, based on hit molecule N-[4-(difluoromethoxy)phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl)sulfanyl]-acetamide, that target the hemopexin-like domain of MMP-9. We identify N-(4-fluorophenyl)-4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-ylthio)butanamide, 3c, as a potent lead (Kd = 320 nM) that is specific for binding to the proMMP-9 hemopexin-like domain. We demonstrate that 3c disruption of MMP-9 homodimerization prevents association of proMMP-9 with both α4β1 integrin and CD44 and results in the dissociation of EGFR. This disruption results in decreased phosphorylation of Src and its downstream target proteins focal adhesion kinase (FAK) and paxillin (PAX), which are implicated in promoting tumor cell growth, migration, and invasion. Using a chicken chorioallantoic membrane in vivo assay, we demonstrate that 500 nM 3c blocks cancer cell invasion of the basement membrane and reduces angiogenesis. In conclusion, we present a mechanism of action for 3c whereby targeting the hemopexin domain results in decreased cancer cell migration through simultaneous disruption of α4β1 integrin and EGFR signaling pathways, thereby preventing signaling bypass. Targeting through the hemopexin-like domain is a powerful approach to antimetastatic drug development.

中文翻译:

用小分子抑制剂靶向潜在基质金属蛋白酶9(proMMP-9)的血红素样结构域可防止形成粘着连接点

靶标特异性的缺乏极大地阻碍了针对多种疾病的基质金属蛋白酶(MMP)抑制剂开发的成功。MMP的催化结构域是高度保守的,而MMP的血红素样结构域对于每个家族成员而言都是唯一的。MMP-9的血红素样结构域通过与CD44和α4β1整联蛋白等细胞表面蛋白的自相互作用和异相互作用增强癌细胞的迁移。这些相互作用激活了EGFR-MAP激酶依赖性信号传导,导致细胞迁移。在这项工作中,我们基于命中分子N- [4-(二氟甲氧基)苯基] -2-[(4-氧代-6-丙基-1 H-嘧啶-2-基)硫烷基]-生成了一个化合物库乙酰胺,靶向MMP-9的血红素样结构域。我们确定N- (4-氟苯基)-4-(4-氧代-3,4,5,6,7,8- hexahydroquinazolin -2-基硫基)丁酰胺,3c中,作为有效铅(ķ d = 320纳米),其具体的与proMMP-9血红素样结构域结合。我们证明Mc-9均二聚体的3c破坏阻止了proMMP-9与α4β1整合素和CD44的缔合,并导致EGFR的解离。这种破坏导致Src及其下游靶蛋白粘着斑激酶(FAK)和paxillin(PAX)的磷酸化降低,这与促进肿瘤细胞的生长,迁移和侵袭有关。使用鸡绒膜尿囊膜体内试验,我们证明了500 nM 3c阻断癌细胞侵袭基底膜并减少血管生成。总之,我们提出了一种针对3c的作用机制,其中针对血红素结构域的作用是通过同时破坏α4β1整联蛋白和EGFR信号传导途径而导致癌细胞迁移减少,从而防止信号传导旁路。通过血红素样结构域靶向是抗转移药物开发的有效方法。
更新日期:2017-10-10
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