The JAK family kinase TYK2 is essential for IL-12, IL-23, and type 1 interferon signaling, which is associated with Th1 and Th17 cell differentiation and activation. The Th1 and Th17 pathways have been implicated in the pathogenesis of psoriasis, psoriatic arthritis, and inflammatory bowel diseases (IBD), thereby making TYK2 an attractive target for the treatment of autoimmune and inflammatory disorders. To maximize therapeutic benefit, we focused our efforts on achieving very high selectivity for inhibition of TYK2 over the related JAK family members JAKs 1-3. Given the high degree of sequence homology between the JAK family members in the catalytic (JH1) domains, we focused on selective inhibition of the allosteric pseudokinase (JH2) domain of TYK2. Using an innovative computationally enabled structure-based approach, we have designed, synthesized, and characterized highly selective small molecule inhibitors of TYK2.<br/>We will describe the discovery of NDI-034858, a highly selective TYK2-JH2 inhibitor with pM binding affinity at TYK2. In cell-based assays, NDI-034858 is a potent inhibitor of TYK2-dependent receptor signaling, including IL-12 induced pSTAT4 in human PBMCs. This presentation will disclose the discovery, preclinical evaluation, and early clinical data of NDI-034858 which is currently in Phase 2 clinical trials.

Discovery of NDI-034858, a highly potent and selective TYK2-JH2 inhibitor for the treatment of autoimmune diseases, through structure-based drug design

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ACS Fall 2022

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