Beyond JAKs SIK Inhibitors

In fact, a Belgium-based company, Galapagos Pharmaceuticals, recently reported preliminary data on its salt-inducible kinase (SIK) therapy, GLPG3970; which is part of their multi-indication SIK inhibitor development program that seeks to “rebalance between pro- and anti-inflammatory pathways rather suppressing the immune system.”

Three salt-inducible kinases have been identified, SIK 1-3, and are thought to reduce certain pro-inflammatory cytokines (such as TNFα) while increasing other anti-inflammatory cytokines (namely IL-10). Known to modulate two families of transcription regulators, histone deacetylases (HDACs) and CREB-regulated transcription coactivators (CRTCs), SIK proteins act as other intracellular kinases by inducing phosphorylation and thus preventing nuclear translocation. Specifically, SIK inhibition frees HDACs and CRTCs from their captive phosphorylated states, allowing downstream blockade of inflammatory mediators and upregulation of anti-inflammatory molecules, respectively.

The above-mentioned research therapy, GLPG3970, is a dual SIK2/3 inhibitor which has preliminarily efficacy data in psoriasis (six-week PASI 50 of 46%), ulcerative colitis (six-week endoscopic 0/1 score of 39%), and rheumatoid arthritis (no efficacy signal at six weeks). While these results may seem anemic to modest, these trials are small, maximally-effective doses have not been determined, and longer primary/secondary end points will need to be explored. Moreover, “rebalancing” the immune system rather than targeting a particular cytokine or receptor, will likely take more time and delicate dosing. Of note, Galapagos Pharmaceuticals reports that initial safety data from these trials was “unremarkable.” Systemic lupus and Sjögren’s trials will start soon.

So it seems that the dermatology community will have to add “SIKs” to its ever-expanding lexicon of -Mabs, -Nibs, JAKs, TYKs, and PDEs.

If one can incorporate all of these monikers into a dinner conversation, they will certainly be a VIP.

Sources:

Source URL: https://ml-eu.globenewswire.com/Resource/Download/c9693fe2-32ef-4ded-85eb-45ee61238a3f

Darling, N., & Cohen, P. Nuts and bolts of the salt-inducible kinases (SIKs). Biochem J. 16 April 2021; 478 (7): 1377–1397. doi: https://doi.org/10.1042/BCJ20200502

Douglas DiRuggiero, DMSc. PA-C, and his wife live in the foothills of Northwest Georgia where he has practiced dermatology for the past 21 years. His three college-aged kids have diverse pursuits which include elementary education, military special forces, and healthcare. They all enjoy traveling, getting outdoors, helping those in need, quoting phrases from "The Office," and putting together complex jigsaw puzzles.