Research Progress on Small-Molecule Inhibitors Targeting Salt-Induced Kinases

Abstract As prominent members of the AMPK family, salt-induced kinases (SIKs) play pivotal roles in regulating cellular metabolism, immune responses, and the tumor microenvironment. Aberrant SIK expression is closely linked to oncogenesis, metabolic disorders, and inflammatory diseases. Consequently, small-molecule inhibitors targeting SIKs have emerged as a major research focus. By blocking SIK kinase activity to modulate downstream signaling pathways—such as the CRTC/CREB and LKB1/AMPK axes—these inhibitors exhibit potent antitumor and immunomodulatory activities. The FDA-approved multi-kinase inhibitors dasatinib and bosutinib strongly inhibit SIKs at low nanomolar concentrations (IC50 < 10 nM); originally developed for leukemia, they have demonstrated robust anti-inflammatory and immunomodulatory efficacy in preclinical models. Furthermore, several newly developed SIK inhibitors display high selectivity and nanomolar potency. This review systematically analyzes and summarizes the structural characteristics and physiological activities of diverse SIK inhibitors reported to date. Additionally, we propose a structural reclassification of these novel inhibitors, evaluating their therapeutic efficacy across various malignancies and discussing their clinical potential. This comprehensive overview aims to accelerate the clinical translation of highly selective SIK inhibitors, offering new avenues for multidimensional interventions in tumor progression.