Structure-Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase...

Salt-inducible kinases (SIK1/2/3) belong to the AMPK family of serine/threonine kinases, and SIK inhibition has been identified as a promising strategy for therapeutic intervention in oncology and immunology. Herein, we describe the use of parallel chemistry approaches to facilitate the development of novel SIK inhibitors. From these efforts, potent pan-SIK inhibitors were identified, as well as compounds which demonstrated biased isoform selectivity toward SIK3, and possessed attractive in vitro ADME properties. To validate the most promising compounds as high-quality chemical tools, cellular target engagement was assessed using NanoBRET assays, and selectivity was investigated across the wider kinome. Finally, the pharmacological effects of several compounds were studied using cellular models of acute myeloid leukemia, resulting in the identification of potent antiproliferative agents. The compounds reported represent high-quality chemical tools of potential value for target validation studies and could serve as effective starting points for a lead optimization campaign.