| PCI-32765 is a selective and covalent inhibitor of Bruton's tyrosine kinase (Btk). The IC50 of PCI-32765 against Btk is 0.5 nM. The IC50s of PCI-32765 against BLK, BMX, CSK, FGR, BRK, HCK, EGFR, YES, and ErbB2 are ranging from 0.5 to 9.4 nM. In DOHH2 cell line in which the BCR pathway can be activated by stimulation with anti-IgG, PCI-32765 inhibits autophosphorylation of Btk, phosphorylation of Btk閳ユ獨 physiological substrate PLCγ, and phosphorylation of a further downstream kinase ERK with IC50s of 11, 29, and 13 nM, respectively. PCI-32765 at concentration of 10 nM potently blocks BCR signaling in human peripheral B cells but does not affect T cell receptor signaling in vitro.[1] Treatment of CD40 or BCR activated chronic lymphocytic leukemia (CLL) cells with PCI-32765 treatment also inhibits Btk phosphorylation and effectively abrogates downstream survival pathways including ERK1/2, PI3K, and NF-ΚB. Moreover, PCI-32765 treatment reduces activation-induced proliferation of CLL cells in vitro, and potently blocks survival signals passed to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact.[2] In vitro, PCI-32765 inhibits BCR-activated primary B cell proliferation with an IC50 of 8 nM. In primary monocytes following FcγR stimulation, PCI-32765 inhibits TNFα, IL-1β and IL-6 production with IC50s of 2.6, 0.5, and 3.9 nM, respectively. In vivo, PCI-32765 dose-dependently and effectively ameliorates arthritic inflammation in a therapeutic collagen-induced arthritis (CIA) model with an ED50 of 2.6 mg/kg/day.[3] In insulinoma-bearing mice in vivo, PCI-32765 administration efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression.[4] In mice with collagen-induced arthritis in vivo, PCI-32765 treatment reduces the level of circulating autoantibodies and completely suppresses disease. Moreover, PCI-32765 also inhibits autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model.[1] |
