Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.

Abstract

Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.

• Authors: Jason A Dubovsky, Kyle A Beckwith, Gayathri Natarajan, Jennifer A Woyach, Samantha Jaglowski, Yiming Zhong, Joshua D Hessler, Ta-Ming Liu, Betty Y Chang, Karilyn M Larkin, Matthew R Stefanovski, Danielle L Chappell, Frank W Frissora, Lisa L Smith, Kelly A Smucker, Joseph M Flynn, Jeffrey A Jones, Leslie A Andritsos, Kami Maddocks, Amy M Lehman, Richard Furman, Jeff Sharman, Anjali Mishra, Michael A Caligiuri, Abhay R Satoskar, Joseph J Buggy, Natarajan Muthusamy, Amy J Johnson, John C Byrd
• Journal: Blood (Blood) Vol. 122 Issue 15 Pg. 2539-49 (Oct 10 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23886836 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Protein-Tyrosine Kinases
• Adenine

Topics

• Adenine (analogs & derivatives)
• Animals
• CD8-Positive T-Lymphocytes (cytology, drug effects, enzymology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• Jurkat Cells
• Leishmaniasis, Cutaneous (drug therapy, immunology)
• Leukemia (drug therapy, immunology)
• Listeriosis (drug therapy, immunology)
• Lymphocyte Activation (drug effects)
• Mice
• Piperidines
• Primary Cell Culture
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Th1 Cells (cytology, drug effects, enzymology)
• Th2 Cells (cytology, drug effects, enzymology)