Ibrutinib (PCI-32765) is a selective, irreversible Btk inhibitor with an IC₅₀ of 0.5 nM^[1].

IC50: 0.5 nM (Btk)

Ibrutinib (PCI-32765) selectively inhibits B-cell signaling and activation. It inhibits autophosphorylation of Btk (IC₅₀=11 nM), phosphorylation of Btk's physiological substrate PLCγ (IC₅₀=29 nM), and phosphorylation of a further downstream kinase, ERK (IC₅₀=13 nM)^[1].
Ibrutinib (PCI-32765) inhibits BCR-activated primary B cell proliferation (IC₅₀=8 nM). Following FcγR stimulation, Ibrutinib (PCI-32765) inhibits TNFα, IL-1β and IL-6 production in primary monocytes (IC₅₀=2.6, 0.5, 3.9 nM, respectively)^[3].
Ibrutinib binds C481 (Cysteine481) of BTK with an ideal IC₅₀ of 0.5?nM. Ibrutinib cannot form a covalent bond with the hydroxyl group of serine, C481S mutation increases the IC₅₀ against BTK-C481S phosphorylation from 2.2?nM to 1?μM^[4].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Ibrutinib (PCI-32765) (3.125-50 mg/kg, p.o.) reduces the level of circulating autoantibodies and completely suppresses disease in mice with collagen-induced arthritis. Ibrutinib (PCI-32765) inhibits autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Ibrutinib (PCI-32765) (3.125-50 mg/kg, p.o.) reduces renal disease and autoantibody production in MRL-Fas(lpr) mice^[1]. Ibrutinib (PCI-32765) (0.1 μM) inhibits activation-induced proliferation of CLL cells, induces selective cytotoxicity in B cells compared with T cells, but alters activation induced T-cell cytokine production^[2]. Ibrutinib (PCI-32765) dose-dependently and potently reverses arthritic inflammation in a therapeutic CIA model with an ED₅₀ of 2.6 mg/kg/day. Ibrutinib (PCI-32765) also prevents clinical arthritis in CAIA models^[3].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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• [1]. Honigberg LA, 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 U S A. 2010 Jul 20;107(29):13075-80.  [Content Brief]

  [2]. Herman SE, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011 Jun 9;117(23):6287-96.  [Content Brief]

  [3]. Chang BY, et al. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 2011 Jul 13;13(4):R115.  [Content Brief]

  [4]. Sun Y, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018 Jul;28(7):779-781.  [Content Brief]