Acalabrutinib is a second-generation, selective and irreversible inhibitor ofBTK (Bruton's tyrosine kinase) with an IC50 of 3 nM and EC50 of 8 nM in a human whole-blood CD69 B cell activation assay. Acalabrutinib has improved pharmacologic features, including favorable plasma exposure, rapid oral absorption, a short half-life, and the absence of irreversible targeting to alternative kinases.
Acalabrutinib is a potent and selective Bruton’s Tyrosine Kinase (BTK) inhibitor with IC50 of 3.0 nM[3], it can bind covalently to C481 in the ATP pocket of BTK irreversibly and then inhibit the BCR signal pathway without effect on EGFR, ITK or TEC signaling[4].
Acalabrutinib could decrease the surface expression of CD86 and CD69 in ex vivo at the doses of 0.34 - 1.8 mg/kg and 0.16 - 1.3 mg/kg respectively. Acalabrutinib also showed other related immune regulation including decreases NK cytolytic function, IFNgamma production and Th cell development[3].
Other study shows that, acalabrutinib inhibits platelet aggregation by plaque with IC50 values of 0.34 ± 0.19 µM through targeting GPIb and GPVI signaling, thus block atherosclerotic plaque-triggered thrombus formation and retaining hemostasis of platelets[5].
In vivo, treatment with acalabrutinib orally at a dose of 12.5 mg/kg twice daily (BID) resulted in tumor growth inhibition in models of diffuse large B cell lymphoma (OCI-LY10) and mantle cell lymphoma (Jeko-1). In OCI-LY10 xenograft model, tumor growth was significantly reduced by acalabrutinib for 28 days[3]. Acalabrutinib has improved pharmacologic features, including favorable plasma exposure, rapid oral absorption, a short half-life, and the absence of irreversible targeting to alternative kinases.
The only clinical study of rheumatoid arthritis commerced in April 2015 and in a 4 weeks study in 70 patients stable on methotrexate[6]. What's more, acalabrutinib was granted accelerated approval by FDA for patients with relapsed or refractory mantle cell lymphoma who have received at least one previous therapy.
作用机制
Acalabrutinib is a Bruton’s Tyrosine Kinase (BTK) inhibitor which forms a covalent bond with cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity, and acalabrutinib appears to have fewer effects than ibrutinib on platelets in aggregometry assays[3].
Acalabrutinib 动物研究
Dose
Mice[3] (p.o.): min = 0.1 mg/kg, max = 30 mg/kg
Dogs[4] (p.o.): min = 2.5 mg/kg, max = 20 mg/kg
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