Ibrutinib, Free Base

Solubility: Soluble in DMSO at 200 mg/mL, soluble in ethanol at 25 mg/mL with slight warming. Ibrutinib, also known as PCI-32765, is a selective and irreversible inhibitor of the enzyme Bruton's tyrosine kinase (BTK). It inhibited BTK potently, with an IC50 of 0.72 nM in enzymology assays and with an IC50 of 10 nM in cellular assay with Ramos cells. It demonstrated preference toward BTK over closely related kinases, blocked B cell function and BTK-dependent processes, and demonstrated clear efficacy in a mouse arthritis model. Young P.R., et al. 'Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase.' ChemMedChem. 2: 58-61 (2007). Ibrutinib blocked B-cell antigen receptor (BCR) signaling in human peripheral B cells at concentrations which did not change T cell receptor signaling, reduced the level of circulating autoantibodies and completely suppressed collagen-induced arthritis in mice, inhibited the production of autoantibodies and the development of kidney disease in the MRL-Fas(lpr) lupus model, and induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. Active site occupancy of BTK was closely correlated with the inhibition of BCR signaling and in vivo efficacy. Honigberg L.A., et al. 'The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.' Proc. Natl. Acad. Sci. USA 107: 13075-13080 (2010). Ibrutinib was well tolerated and had significant activity in patients with relapsed/refractory B-cell malignancies. Advani R.H., et al. 'Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.' J. Clin. Oncol. 31: 88-94 (2013).