Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold.
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DOI：
10.1021/acs.jmedchem.5b01171
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发表时间：
2015-12
影响因子：
7.3
通讯作者：
Rafaela Gladysz;Y. Adriaenssens;H. De Winter;J. Joossens;A. Lambeir;K. Augustyns;P. Van der Veken
中科院分区：
文献类型：
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作者：
Rafaela Gladysz;Y. Adriaenssens;H. De Winter;J. Joossens;A. Lambeir;K. Augustyns;P. Van der Veken
尿激酶型纤溶酶原激活剂(UPA)是多种癌症的生物标志物和治疗靶点。通过抑制实体瘤的生长和/或转移，它被认为是一种很有前途的、无细胞毒性的癌症治疗方法。早些时候，我们报道了改进的底物活性筛选(MSAS)方法，并将其应用于鉴定与uPA的S1口袋具有亲和力的片段。在这里，这些片段被转化为一类新型的带有咪唑并[1，2-a]吡啶支架的uPA抑制剂。探索了在这种支架周围抑制uPA的SAR，并且该系列中最好的化合物对相关的胰酶样丝氨酸蛋白酶(凝血酶、tPA、FXA、纤溶酶、血浆激肽释放酶、胰蛋白酶、FVIIa)具有纳米分子的uPA亲和力和选择性。最后，通过装饰支架结构将片段转化为小分子的方法在概念上是简单的，可以预期在基于片段的药物设计中广泛适用。
Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's S1 pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-a]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design.