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: Lee A Honigberg, Ashley M Smith, Mint Sirisawad, Erik Verner, David Loury, Betty Chang, Shyr Li, Zhengying Pan, Douglas H Thamm, Richard A Miller, Joseph J Buggy
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 29 Pg. 13075-80 (Jul 20 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20615965 (Publication Type: Journal Article)

Chemical References

• Autoantibodies
• Benzofurans
• Piperidines
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Receptors, Antigen, B-Cell
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• Btk protein, mouse
• Adenine

Topics

• Adenine (analogs & derivatives)
• Administration, Oral
• Agammaglobulinaemia Tyrosine Kinase
• Animals
• Arthritis, Experimental (drug therapy)
• Autoantibodies (biosynthesis)
• Autoimmune Diseases (drug therapy, enzymology)
• B-Lymphocytes (drug effects, enzymology, immunology)
• Benzofurans (administration & dosage, chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Dogs
• Humans
• Lymphocyte Activation (drug effects)
• Lymphoma, B-Cell (drug therapy, enzymology)
• Mice
• Piperidines
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (administration & dosage, chemistry, pharmacology, therapeutic use)
• Pyrimidines (administration & dosage, chemistry, pharmacology, therapeutic use)
• Receptors, Antigen, B-Cell (immunology)
• Signal Transduction (drug effects)
• Treatment Outcome