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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- 作者：Rafaela Gladysz ; Yves Adriaenssens ; Hans De Winter ; Jurgen Joossens ; Anne-Marie Lambeir ; Koen Augustyns ; Pieter Van der Veken
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：December 10, 2015
- 年：2015
- 卷：58
- 期：23
- 页码：9238-9257
- 全文大小：703K
- ISSN：1520-4804
文摘
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鈥檚 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.