Ibrutinib is a highly selective Bruton's tyrosine kinase (Btk) irreversible inhibitor.PCI-32765 (Ibrutinib) is a selective and irreversible pyrrolopyrimidine-based inhibitor of BTK with IC50 of 0.5 nM. [1] PCI-32765 binds irreversibly to Cys-481 in BTK and thus is only active with other kinases with such a modifiable cysteine residue. In DOHH2 cells, in which the BCR pathway can be activated by anti-IgG, PCI-32765 inhibits autophosphorylation of BTK (IC50, 11 nM), BTK's physiological substrate, PLCg (IC50, 29 nm), and downstream ERK (IC50, 13 nm). 

Applicatiao of Ibrutinib

PCI-32765 (Ibrutinib) is a high potent irreversible BTK inhibitor with an IC50 of 0.46 nM for the purified Btk.PCI-32765 (Ibrutinib) is highly active and well tolerated in CLL/SLL pts irrespective of high risk genomic abnormalities. Although follow-up is short, the high response rate and very low progression rate suggests that PCI-32765 (Ibrutinib) may be an important new targeted treatment approach for CLL pts. In ex vivo assays with whole bold, PCI-32765 (Ibrutinib) prevents the activation of human BCR with an IC50 of about 0.2 μM, while not influencing the activation of T cell. Treatment of CD40 or BCR activated CLL cells with PCI-32765 (Ibrutinib) results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 (Ibrutinib) prevents activation-induced proliferation of CLL cells in vitro, and effectively inhibits survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. PCI-32765 is originally developed by Pharmacyclics. And participants is been invited for the phase I clinical trials.

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