Acalabrutinib

A novel, irreversible, covalent second-generation BTK inhibitor with IC50 of 3 nM; more potent and selective than ibrutinib, and does not inhibit EGFR, Itk or Txk; inhibits tyrosine phosphorylation of downstream targets of ERK, IKB, and AKT, in the in vitro signaling assay on primary human CLL cells; inhibits anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg in mice; has promising safety and efficacy profiles for CLL treatment; orally active.Blood Cancer Approved (In Vitro) :Acalabrutinib (ACP-196) inhibits tyrosine phosphorylation of downstream targets of ERK, IKB, and AKT, in the in vitro signaling assay on primary human CLL cells. In the human CLL NSG xenograft model, Acalabrutinib demonstrates on-target effects including decreased phosphorylation of PLCγ2, ERK and significant inhibition of CLL cell proliferation.Acalabrutinib inhibits purified BTK with an IC50 of 3 nM and an EC50 of 8 nM in a human whole-blood CD69 B cell activation assay. Acalabrutinib has improved target specificity over ibrutinib with 323-, 94-, 19-, and 9-fold selectivity over the other TEC kinase family members (ITK, TXK, BMX, and TEC , respectively) and no activity against EGFR. (In Vivo) :Acalabrutinib (100 mg twice per day) assessed for thrombus formation at injured arterioles of the mice, exhibits more selective for inhibiting BTK and has virtually no inhibition of platelet activity.