In vitro
As a selective and irreversible Btk inhibitor, PCI-32765 can inhibit Bruton tyrosine kinase (Btk) with IC50 of 0.46 nM. As Bruton tyrosine kinase (Btk) is specifically required for BCR signaling, PCI-32765 can block BCR signaling pathway by inhibiting Bruton tyrosine kinase (Btk). In CD40 or BCR activated CLL cells, PCI-32765 can inhibit BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-kappaB. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation with IC50 of 8 nM. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. As B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL), PCI-32765 inhibits activation-induced proliferation of CLL cells by inhibiting BTK, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-alpha), fibronectin engagement, and stromal cell contact.
In vivo
In MRL-Fas(lpr) lupus model, 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.
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