In vitro: In the in vitro signaling assay on primary human CLL cells, acalabrutinib inhibits tyrosine phosphorylation of downstream targets of ERK, IKB, and AKT. Acalabrutinib demonstrates higher selectivity for BTK with IC50 determinations on nine kinases with a cysteine residue in the same position as BTK. Importantly, unlike ibrutinib, acalabrutinib does not inhibit EGFR, ITK, or TEC. acalabrutinib has no effect on EGFR phosphorylation on tyrosine residues Y1068 and Y1173. Compared with ibrutinib, acalabrutinib has much higher IC50(>1000 nM) or virtually no inhibition on kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.
In vivo: oral administration of ACP-196 in mice results in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model is used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 inhibits CD86 expression >90% at 3h postdose.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||80 mg/mL in DMSO|
Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor.
Wu J, et al. J Hematol Oncol. 2016 Mar 9;9:21. PMID: 26957112.
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.
Byrd JC, et al. N Engl J Med. 2016 Jan 28;374(4):323-32. PMID: 26641137.
|Related BTK Products|
Remibrutinib (LOU064) is a potent and highly selective covalent Inhibitor of Bruton's Tyrosine Kinase (BTK) with IC50 value of 1 nM.
Tolebrutinib, also known as SAR442168, is a Bruton tyrosine kinase (BTK) inhibitor, with IC50 values of 0.4 nM and 0.7 nM in Ramos B cells and HMC microglia cells, respectively.
Orelabrutinib is an orally active and irreversible inhibitor of Bruton's tyrosine kinase (BTK).
Zanubrutinib (BGB-3111) is a potent and highly selective small molecule inhibitor of Bruton's tyrosine kinase (BTK).
ARQ 531 is a potent reversible inhibitor of BTK (IC50 = 0.85 nM), exhibits potent antitumor activity in ibrutinib-resistant diffuse large B-cell lymphoma.
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