1 research outputs found
Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2‑<i>a</i>]pyridine Scaffold
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 imidazoÂ[1,2-<i>a</i>]Âpyridine 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