Identification of highly potent and selective Tyk2 inhibitors for the treatment of autoimmune diseases through structure-based drug design (THER2P.961)

The JAK family kinase Tyk2 is essential for IL-12 and IL-23 signaling, which are associated with Th1 and Th17 cell differentiation and activation. The Th1 and Th17 pathways have been implicated in the pathogenesis of psoriasis and inflammatory bowel diseases (IBD) thereby making Tyk2 a highly attractive target for the treatment of these disorders. However, given the high degree of sequence homology between the JAK family kinases, designing potent and selective Tyk2 inhibitors remains a challenge. Using an innovative structure-based approach, we have designed, synthesized and characterized small molecule inhibitors optimized for JAK family selectivity using computational free energy perturbation (FEP) methods and medicinal chemistry SAR. We have identified selective Tyk2 inhibitors with pM activity against Tyk2 (K i =140-520 pM) and >100 fold selectivity over JAK2 and JAK1 with more moderate selectivity over JAK3. These analogs are orally bioavailable (85%F) with suitable drug-like properties. NDI-031232 was determined to be highly selective across 359 kinases, and is a potent inhibitor of IL-12 induced pSTAT4 in hPBMCs (IC 50 =17 nM) and IL-12 induced IFNg in human whole blood (IC 50 =520 nM). NDI-031232 also demonstrated robust efficacy in blocking IL-12-mediated IFNg production in an ex vivo mouse model. Therefore, selective inhibitors of Tyk2 retain the anti-inflammatory activity while reducing potential for dose-limiting side effects observed with non-selective JAK inhibitors.