title: The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.
abstract: Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.
authors.affiliation: Pharmacyclics, Sunnyvale, CA 94085-4521, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Honigberg
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Smith
authors.forename: Mint
authors.initials: M
authors.lastname: Sirisawad
authors.forename: Erik
authors.initials: E
authors.lastname: Verner
authors.forename: David
authors.initials: D
authors.lastname: Loury
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: Shyr
authors.initials: S
authors.lastname: Li
authors.forename: Zhengying
authors.initials: Z
authors.lastname: Pan
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Thamm
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000201:enzymology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D001572:Benzofurans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D001572:Benzofurans; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine