A dock derived compound against laminin receptor (37 LR) exhibits anti-cancer properties in a prostate cancer cell line model.
A dock derived compound against laminin receptor (37 LR) exhibits anti-cancer properties in a prostate cancer cell line model.
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DOI：
10.18632/oncotarget.23236
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发表时间：
2018-01-19
期刊：
影响因子：
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通讯作者：
Figueiredo ML
中科院分区：
文献类型：
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作者：
Umbaugh CS;Diaz-Quiñones A;Neto MF;Shearer JJ;Figueiredo ML
层粘连蛋白受体（67 LR）是由37 kDa前体（37 LR）衍生的67 kDa蛋白。LR与乳腺癌、前列腺癌和结肠癌等多种癌症的进展、侵袭性和化疗复发有很强的临床相关性。37/67 LR促进癌细胞侵袭的能力通过其在内皮细胞中转导物理化学和机械传感信号以及调节血管生成的能力进一步增强。最近有研究表明，37/67 LR可调节分泌的糖蛋白色素上皮衍生因子（PEDF）的抗血管生成潜能。恢复PEDF平衡是一个理想的治疗结果，我们试图确定一种小分子，它可以重现已知的PEDF信号特性，但没有肽制剂或基因传递安全性验证的额外并发症。我们使用了一种计算机药物发现方法来定位PEDF和37lr之间的相互作用界面。经过基于细胞的反筛选和结合验证，我们表征了hit化合物的抗活力、PEDF信号相关基因的激活、抗伤口愈合和抗癌信号特性。该hit化合物作为治疗肿瘤生长和抑制血管生成的先导化合物具有未来发展的潜力。
Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals in endothelial cells and modulate angiogenesis. Recently, it was demonstrated that 37/67 LR modulates the anti-angiogenic potential of the secreted glycoprotein pigment epithelium-derived factor (PEDF). Restoration of PEDF balance is a desirable therapeutic outcome, and we sought to identify a small molecule that could recapitulate known signaling properties of PEDF but without the additional complications of peptide formulation or gene delivery safety validation. We used an in silico drug discovery approach to target the interaction interface between PEDF and 37 LR. Following cell based counter screening and binding validation, we characterized a hit compound’s anti-viability, activation of PEDF signaling-related genes, anti-wound healing, and anti-cancer signaling properties. This hit compound has potential for future development as a lead compound for treating tumor growth and inhibiting angiogenesis.