The Development of Selective Chemical Probes for Serine Arginine Protein Kinase 3

The serine arginine protein kinases (SRPKs) are a family of kinases whose irregular function is implicated in cancer and viral infections. While the roles of SRPK1 and SRPK2 in disease are well established, much less is known about SRPK3. There are several studies implicating SRPK3 in breast cancer, but the mechanism is still unknown. This work describes the first-reported SRPK3 chemical probes that show excellent selectivity over the other SRPKs. 1-(4-cyanophenyl)-3-phenylurea was identified as an initial hit for SRPK3 through a kinase screen. Subsequent rounds of in silico docking, medicinal chemistry optimization, and biochemical assays were performed to increase its potency and selectivity for SRPK3. Six top compounds were identified that displayed single digit micromolar IC₅₀ values in SRPK3 activity assays and negligible inhibition of SRPK1 or SRPK2. These six compounds demonstrated impairment of breast cancer cell viability that correlated with their biochemical IC₅₀ values, suggesting that they can be used as tools to study the biological functions of SRPK3 in breast cancer. With an enhanced understanding of SRPK3's biological function, it may emerge as a meaningful drug target, wherein our top inhibitors could be further optimized to produce novel cancer therapeutics.