Small-molecule inhibition of the uPAR·uPA interaction: synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis.
Small-molecule inhibition of the uPAR·uPA interaction: synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis.
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DOI：
10.1016/j.bmc.2012.12.047
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Meroueh SO
中科院分区：
文献类型：
--
作者：
Mani T;Wang F;Knabe WE;Sinn AL;Khanna M;Jo I;Sandusky GE;Sledge GW Jr;Jones DR;Khanna R;Pollok KE;Meroueh SO
uPAR·uPA蛋白-蛋白相互作用（PPI）参与信号传导和蛋白水解，促进肿瘤的侵袭和转移。先前的研究已经从商业化学文库的计算机筛选中鉴定出4（IPR-803），并且在竞争生化测定和侵袭细胞研究中显示该化合物抑制uPAR·uPA PPI。在这里，我们合成4，以评估在小鼠乳腺癌转移模型中的体内药代动力学（PK）和疗效研究。首先，我们使用荧光偏振和饱和转移差（STD）NMR显示，4以0.2 μM的亚微摩尔亲和力直接与uPAR结合。我们发现4阻断乳腺MDA-MB-231的侵袭，并抑制细胞外基质（ECM）的基质金属蛋白酶（MMP）分解。4的衍生物也以浓度依赖性方式抑制MMP活性并阻断侵袭。4还损害MDA-MB-231细胞的粘附和迁移。在NOD-SCID小鼠中进行的广泛体内PK研究显示，半衰期接近5小时，峰浓度为5 μM。在长达10小时的肿瘤组织中检测到类似水平的抑制剂。在其乳房脂肪垫中接种高度恶性TMD-MDA-MB-231的雌性NSG小鼠显示4个受损的肺转移，与未处理小鼠的10个相比，仅4个处理小鼠显示严重或显著的转移。化合物4是用于开发具有增强的PK参数和更大功效的化合物的有前景的模板。
The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 hours and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 hours. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.
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影响因子：
8
作者：
Patel, J. B.;Appaiah, H. N.;Nakshatri, H.
通讯作者：
Nakshatri, H.
影响因子：
4.8
作者：
Mertens, Haydyn D. T.;Kjaergaard, Magnus;Ploug, Michael
通讯作者：
Ploug, Michael
影响因子：
4.8
作者：
Gardsvoll, Henrik;Jacobsen, Benedikte;Ploug, Michael
通讯作者：
Ploug, Michael
影响因子：
4
作者：
Khanna M;Wang F;Jo I;Knabe WE;Wilson SM;Li L;Bum-Erdene K;Li J;W Sledge G;Khanna R;Meroueh SO
通讯作者：
Meroueh SO
人尿激酶纤溶酶原激活剂与其受体复合物的结构
影响因子：
56.9
作者：
Huai, Q;Mazar, AP;Huang, MD
通讯作者：
Huang, MD