生物活性

• 靶点	BTK IC50:0.5nM

• 描述Btk (Bruton tyrosine kinase), a non-receptor tyrosine kinase, is specifically required for BCR signaling which contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. Ibrutinib, also called as PCI-32765 or imbruvica, is a potent Btk inhibitor with IC50 of 0.5 nM (measured by 33P filtration binding assay), modestly potent to Blk (IC₅₀= 0.5 nM), Bmx (IC₅₀= 0.8 nM), CSK (IC₅₀= 2.3 nM), FGR (IC₅₀= 2.3 nM), BRK (IC₅₀= 3.3 nM), HCK (IC₅₀= 3.7 nM), less potent to EGFR (IC₅₀= 5.6 nM), Yes (IC₅₀= 6.5 nM), ErbB2 (IC₅₀= 9.4 nM), ITK (IC₅₀= 10.7 nM). Ibrutinib can selectively inhibit B-cell signaling and activation, including inhibition of autophosphorylation of Btk, phosphorylation of Btk's physiological substrate PLCγ and phosphorylation of a further downstream kinase ERK, in DOHH2 cells. Continuous exposure to 10 nM Ibrutinib for 18h completely prevented up-regulation of CD69, the B-cell activation marker. In vivo study shows that Btk inhibition by Ibrutinib is efficacious for autoimmune disease animal model. Oral treatment daily for 11 days with 12.5 mg/kg of Ibrutinib can inhibit collagen-induced arthritis in mice^[1]. Up to now, Ibrutinib is approved to the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graft versus host disease^[2].
• 作用机制Ibrutinib can bind covalently to a cysteine residue (Cys-481) in the active site, leading to potent and irreversible inhibition of Btk enzymatic activity^[3]. Notice: BMX, EGFR, ErbB2, ITK, JAK3,AK3 and TEC is the kinase that contains a cysteine residue aligning with Cys-481 same as Btk, resulting in the binding with Ibrutinib^[1].

• 动物研究
  剂量	Mice[3]: min = 2.5 mg/kg, max = 25 mg/kg
  给药途径	p.o.