Characterization of ARTS-011, a potent and selective TYK2 inhibitor for the treatment of inflammatory disease

Abstract The JAK family kinase TYK2 is a key regulator of IL-12 and IL-23 signaling pathways, which have been shown to be involved in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, lupus and inflammatory bowel diseases (IBD). TYK2 inhibition is an attractive therapeutic strategy for human autoimmune diseases. Here, we report a potent oral TYK2 allosteric inhibitor ARTS-011, with high selectivity and potency through optimized binding to the JH2 regulatory domain of the TYK2 protein. ARTS-011 potently binds to TYK2 JH2 domain in binding assay and inhibits IL-23 and IFNα/β induced reporter activation depending on TYK2 kinase. ARTS-011 also inhibits IFNα triggered pSTAT5 potently in human whole blood assay. In addition, ARTS-011 excellent selectivity against other JAK family kinases and panels of receptors, transporters, ion channels, CYP enzymes and the hERG channel. Furthermore, ARTS-011 was also investigated in multiple animal models including IL12/18-induced serum IFNγ mouse model, IL-23-induced mouse psoriasis model and CD40 antibody-induced mouse inflammatory bowel disease (IBD) model. In vivo pharmacodynamic study indicates that ARTS-011 significantly reverses IL12/18-induced IFNγ production in mouse. ARTS-011 also significantly reduces the ear swelling in a dose-dependent manner in IL-23-induced mouse psoriasis model. Lastly, ARTS-011 was highly efficacious in anti-CD40 antibody induced mouse IBD model. In summary, ARTS-011 is a highly selective, potent and orally available small molecule TYK2 inhibitor with suitable pharmaceutical properties as potential therapeutics in inflammatory disorders.