title: 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.affiliation: Department of Internal Medicine, Division of Hematology.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Dubovsky
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Beckwith
authors.forename: Gayathri
authors.initials: G
authors.lastname: Natarajan
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.forename: Samantha
authors.initials: S
authors.lastname: Jaglowski
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhong
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hessler
authors.forename: Ta-Ming
authors.initials: TM
authors.lastname: Liu
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.forename: Karilyn M
authors.initials: KM
authors.lastname: Larkin
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stefanovski
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Chappell
authors.forename: Frank W
authors.initials: FW
authors.lastname: Frissora
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Smith
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Smucker
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Flynn
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lehman
authors.forename: Richard
authors.initials: R
authors.lastname: Furman
authors.forename: Jeff
authors.initials: J
authors.lastname: Sharman
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000276:immunology; D007938:Leukemia / Q000188:drug therapy / Q000276:immunology; D008088:Listeriosis / Q000188:drug therapy / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010880:Piperidines; D061251:Primary Cell Culture; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000225:Adenine