Structure activity relationship exploration of imidazo[1,2-a]pyridine series to reverse isoform selectivity and...

The salt-inducible kinase (SIK) family encompasses three isoforms, SIK1, SIK2, and SIK3, which are members of the AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. SIK inhibition has emerged as a potential therapeutic approach across multiple indications, as SIKs regulate a diverse set of physiological processes such as metabolism, bone remodeling, immune response, malignancies, skin pigmentation, and circadian rhythm. Within isoform-specific SIK inhibitors there is a need to understand the distinct role of each protein, and here we describe the first SIK1 selective inhibitors. Beginning with a high-throughput screening (HTS) hit that exhibited pan-SIK inhibition, structure-activity relationship (SAR) investigation led to the identification of a substitution pattern on a phenyl ring that increased both potency on SIK1 and selectivity against SIK2 and SIK3. Further optimization of isoform selectivity led to compound 27, a subnanomolar inhibitor of SIK1 in biochemical assays that exhibited more than 100-fold selectivity against SIK2 and SIK3. Isoform selectivity of 27 was confirmed in a cellular context. Identification of compound 27 provided a SIK1-selective compound to investigate the role of SIK1 in biological processes mediated by SIKs; however, activity of 27 on other kinases, in particular tyrosine kinases, should not be neglected upon data interpretation.