MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core

The highly conserved catalytic sites in protein kinases
make it
difficult to identify ATP competitive inhibitors with kinome-wide
selectivity. Serendipitously, during a dedicated fragment campaign
for the focal adhesion kinase (FAK), a scaffold that had lost its
initial FAK affinity showed remarkable potency and selectivity for
serine-arginine-protein kinases 1–3 (SRPK1–3). Non-conserved
interactions with the uniquely structured hinge region of the SRPK
family were the key drivers of the exclusive selectivity of the discovered
fragment hit. Structure-guided medicinal chemistry efforts led to
the SRPK inhibitor MSC-1186, which fulfills all hallmarks
of a reversible chemical probe, including nanomolar cellular potency
and excellent kinome-wide selectivity. The combination of MSC-1186 with CDC2-like kinase (CLK) inhibitors showed additive attenuation
of SR-protein phosphorylation compared to the single agents. MSC-1186 and negative control (MSC-5360) are
chemical probes available via the Structural Genomics Consortium chemical
probe program (https://www.sgc-ffm.uni-frankfurt.de/).