Topical selective TYK2 inhibition attenuates inflammation and clinical symptoms in a mouse model of human psoriasis

Abstract Psoriasis is a chronic skin condition, that affects ~8M patients in the United States. A majority (~7M) of patients suffer from mild to moderate form of disease that lacks safe & effective treatment options. Although antibodies targeting Th1/Th17 cytokines (eg IL12/IL23/IL17) are highly effective in moderate to severe psoriasis, they are not prescribed to mild to moderate patients due to high costs & safety concerns. There is a huge unmet need for developing safe and effective non-steroidal topical therapies. Small molecule inhibitors of Th1/Th17 pathways with optimal topical drug like properties can effectively address patient needs; making TYK2 inhibitors (TYK2i) attractive candidates for treating mild to moderate psoriasis. However, given the high degree of structural similarity among JAK family, designing topical selective TYK2i have remained a challenge. Using an innovative structure based approach, we have designed, synthesized and characterized TYK2i optimized for topical drug like properties and JAK family selectivity using free energy perturbation (FEP) methods and medchem SAR. We have identified TYK2i with pM to low nM potencies that are highly selective for TYK2 among 468 kinases. These analogs have enhanced topical bioavailability with suitable drug like properties. In a mouse model of psoriasis, these analogs dose-dependently suppressed PASI clinical scores, ear & back skin thickness and inflammation. Additionally, skin histology showed significant attenuation of epidermal thickening and pSTAT activation suggesting that topical TYK2 inhibition retains anti-inflammatory activity while eliminating potential for dose-limiting side effects observed with systemic non-selective TYK2 or other JAK inhibitors. This research has been fully funded by Alembic Pharmaceuticals Ltd., including salary support to all authors.