SIK inhibitor OMX-0407

An orally bioavailable inhibitor of the salt-inducible kinase 3 (SIK3), with potential antineoplastic and chemosensitizing activities. Upon oral administration, SIK3 inhibitor OMX-0407 targets, binds to and blocks the activity of SIK3. This prevents SIK3-mediated signaling, inhibits SIK3-triggered phosphorylation of histone deacetylase 4 (HDAC4) and inhibits the associated transcriptional activity of NF-kB. This inhibits pro-survival signaling mediated by SIK3-HDAC4-nuclear factor kappa B (NF-kB) signaling and potentiates death receptor (DR)-mediated apoptosis in SIK3-overexpressing tumor cells. OMX-0407 may enhance tumor sensitivity to other chemotherapeutic agents. In addition, OMX-0407 repolarizes the tumor microenvironment (TME) by strongly decreasing regulatory T cells (Tregs) and M2-polarized macrophages while not affecting the peripheral T cells. This reduces the immunosuppressive TME and increases cytotoxic T-cell activity, thereby inducing an anti-tumor immune response. SIK3, a serine/threonine kinase belonging to the AMP-activated protein kinase (AMPK)-related family, is required for bipolar mitotic spindle formation; it is overexpressed in a variety of tumor cell types. It also promotes NF-kB nuclear translocation and stabilization and activation, leading to increased tumor cell survival.