SIK1 x SIK2

Inhibition of salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 represents a new potential therapeutic approach for autoimmune and inflammatory disease treatment via modulation of pro-inflammatory and immunoregulatory pathways, particularly inhibition of SIK2 and SIK3. After discovering a new chemotype for SIK inhibition, further optimization of potency, selectivity, ADMET and PK properties resulted in a 1,6-naphtyridine containing molecule GLPG4876 (7). However, 7 was clastogenic when examined in vivo in rat micronucleus assays, preventing further development. Overlay of 7 with GLPG3970 (6) within the SIK3 protein structure inspired the design of pyridine derivatives, leading to the identification of GLPG4970 (8). Compound 8 was negative in genotoxicity screening assays and demonstrated potent SIK2/SIK3 inhibition, for which isoform selectivity was determined in a cellular context. Compound 8 displayed improved potency compared with previously reported SIK inhibitors in biochemical and phenotypic cellular assays, and showed dose-dependent activity in disease relevant mouse pharmacological models of colitis.

The salt-inducible kinases (SIKs), a family of serine/threonine kinases, are emerging endocrine regulators. The 3 isoforms, SIK1, SIK2, and SIK3, compose a subfamily of the 5′ adenosine monophosphate-activated protein kinase-related kinases. The SIKs have multiple conserved protein kinase A phosphorylation sites by which they are regulated. Further, a family of well-characterized SIK targets is the cAMP response element binding protein regulated transcription coactivators, which promote cAMP response element-binding protein transcription. As such, the SIKs participate in several cAMP-dependent pathways, including classical GPCR cascades characteristic of endocrine signaling. This review discusses the currently known roles of the SIKs in the endocrine system. Specifically, the research on SIKs in this field up to this point has focused on the adrenal glands, ovary, pancreas, pineal gland, immune function of the thymus, parathyroid hormone signaling in the bone, and hypothalamic regulation of the circadian rhythm and endocrine axes. Furthermore, this review highlights the remaining questions in these areas and the glands in which little to no SIK research has been published: the testis, pituitary, thyroid gland, and parathyroid glands.

Salt-inducible kinases (SIKs) are a subfamily of the adenosine monophosphate-activated protein kinase-related kinase family. To be activated, SIKs require phosphorylation in the catalytic kinase domain by liver kinase B1. In response to extracellular stimulations, their activity can be further regulated through phosphorylation by protein kinase A (PKA), and Ca2+/calmodulin-dependent protein kinases. PKA-mediated SIK inhibition is a major link between G-protein coupled receptor activation and the target gene transcription program. All 3 SIK isoforms—SIK1, SIK2, and SIK3—are expressed in adipocytes, with SIK2 being the most abundant in both rodents and humans. SIKs play essential roles in maintaining adipose tissue homeostasis by regulating physiological processes involving insulin signaling, glucose uptake, lipogenesis, and thermogenesis. Each SIK isoform could play both redundant and unique roles in these physiological processes. Many of the substrates that mediate their physiological functions in adipocytes have been characterized, and downstream mechanisms of action have also been proposed. However, due to the functional redundancy of SIKs, a major challenge is to delineate their isoform-specific roles in adipose tissue in vivo using genetic mouse models. In addition, common genetic variants and rare mutations in the SIK genes have been identified to be associated with metabolic, cardiovascular, and developmental conditions, suggesting a translational implication for human disease that deserves investigation. Furthermore, small molecular SIK inhibitors have been developed and have shown therapeutic potential in multiple disease areas. Evaluation of their metabolic and cardiovascular effects will be required for future clinical development of SIK inhibitors.