Characterization of the dual ITK/JAK3 small molecule covalent inhibitor ATI-2138

• Published in: The Journal of pharmacology and experimental therapeutics 2025-02, Vol.392 (2), p.100054, Article 100054
• Main Authors: Kaul, Aparna, Hope, Heidi, Xu, Canxin, Basavalingappa, Rakesh, Binz, Sara, Boily, Chad, Bradley, Zachary, Burt, David, Emanuel, Catherine, Fairchild, Jacob, Egan, Sarah, Hildebrand, Anne, Howell, Victoria, Huang, Huiyan, Huff, Emma, Iken, Abbygail, Knapik, Stephanie, Lawrence, Melissa, Lin, Huawen, Lu, Jessea Wenjie, Mattingly, Jonathan, McGraw, Dean, McGraw, Nancy, Mnich, Stephen, Morton, William, Ortmann, Robert, Piccinni-Ash, Tyler, Saer, Rafael, da Silva, Cristiane Secca, Stillwell, Loreen, Taylor, William, Warner, Elizabeth, Wrightstone, Ann, Jacobsen, E. Jon, Anderson, David R., Monahan, Joseph
• Format: Article
• Language: English
• Subjects: ▪
• ISSN: 0022-3565
• DOI: 10.1016/j.jpet.2024.100054

ATI-2138 is a novel investigational covalent inhibitor of interleukin-2–inducible T cell kinase (ITK), resting lymphocyte kinase, and Janus kinase 3 (JAK3) in development for the treatment of autoimmune and inflammatory diseases. In this study, we evaluated the inhibitory effects of ATI-2138 on ITK and JAK3 signaling in cells and preclinical animal models and assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ATI-2138 in healthy human participants. ATI-2138 potently, selectively, and irreversibly inhibited ITK, resting lymphocyte kinase, and JAK3 kinases with similar potency observed against ITK and JAK3 in biochemical and immune cell signaling assays. Translation from cellular and whole blood studies to in vivo models was observed, wherein ATI-2138 demonstrated disease-modifying activity in 2 rodent models of arthritis and an adoptive T cell model of colitis. In single and multiple ascending dose studies in healthy human participants, ATI-2138 had a favorable safety profile with linear pharmacokinetics. Biomarkers linked to both ITK and JAK3 activity were inhibited with ATI-2138 in an exposure-, dose-, and time-dependent manner and correlated with enzyme, cellular, whole blood, and rodent studies, thereby demonstrating predictive translational properties. As a potential first-in-class dual inhibitor of ITK and JAK3, ATI-2138 may be useful in the treatment of immunoinflammatory diseases. ATI-2138 is a novel covalent inhibitor of interleukin-2–inducible T cell kinase (ITK)/resting lymphocyte kinase and Janus kinase 3 (JAK3). ATI-2138 inhibits JAK3 and ITK in enzyme and functional cellular assays, demonstrates disease-modifying activity in rodent models of arthritis and colitis, and inhibits biomarkers linked to both ITK and JAK3 activity in healthy human participants. With this dual kinase activity against components of the inflammatory signaling pathway, ATI-2138 has the potential for enhanced therapeutic efficacy in the treatment of autoimmune and chronic inflammatory disease.