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

IF 3.1 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of Pharmacology and Experimental Therapeutics Pub Date : 2025-02-01 Epub Date: 2024-12-09 DOI:10.1016/j.jpet.2024.100054

Aparna Kaul, Heidi Hope, Canxin Xu, Rakesh Basavalingappa, Sara K Binz, Chad Boily, Zachary Bradley, David Burt, Catherine Emanuel, Jacob Fairchild, Sarah Egan, Anne Hildebrand, Victoria Howell, Huiyan Huang, Emma Huff, Abbygail Iken, Stephanie Knapik, Melissa Lawrence, Huawen Lin, Jessea Wenjie Lu, Jonathan Mattingly, Dean McGraw, Nancy McGraw, Stephen Mnich, William Morton, Robert Ortmann, Tyler Piccinni-Ash, Rafael Saer, Cristiane Secca da Silva, Loreen Stillwell, William Taylor, Elizabeth Warner, Ann Wrightstone, E Jon Jacobsen, David R Anderson, Joseph Monahan

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引用次数: 0

Abstract

Aclaris Therapeutics Inc (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. SIGNIFICANCE STATEMENT: Aclaris Therapeutics Inc (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 these inflammatory signaling pathway, ATI-2138 has the potential for enhanced therapeutic efficacy in the treatment of autoimmune and chronic inflammatory disease.

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来源期刊

Journal of Pharmacology and Experimental Therapeutics 医学-药学

CiteScore

6.90

自引率

0.00%

发文量

115

审稿时长

1 months

期刊介绍： A leading research journal in the field of pharmacology published since 1909, JPET provides broad coverage of all aspects of the interactions of chemicals with biological systems, including autonomic, behavioral, cardiovascular, cellular, clinical, developmental, gastrointestinal, immuno-, neuro-, pulmonary, and renal pharmacology, as well as analgesics, drug abuse, metabolism and disposition, chemotherapy, and toxicology.