Background:

IC50: 3 nM

ACP-196 is an irreversible BTK inhibitor.

Bruton's tyrosine kinase (BTK) is a critical component of B cell receptor signalling and functions as an key regulator of cell proliferation and survival in various B cell malignancies.

In vitro: Previous study showed that ACP-196 had high selectivity for Btk when tested against a panel of 395 non-mutant kinases, which was associated with the reduced intrinsic reactivity of ACP-196's electrophile. Moreover, ACP-196 could not inhibit EGFR, Itk or Txk, which is unlike ibrutinib. In addition, the phosphoflow assays on EGFR expressing cell lines furthre confirmed ibrutinib's EGFR inhibition without inhibition observed for ACP-196 [1].

In vivo: Oral administration of ACP-196 in mice led to the dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes. In addition, a similar model was used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg, and the results showed that ACP-196 and ibrutinib inhibited CD86 expression >90% at 3h and around 50% at 24h postdose [1].

Clinical trial: Previous study found that ACP-196 at an oral dose of 100 mg/day showed more than 90% target coverage over a 24h period in healthy volunteers. Moreover, the Btk occupancy and regulation of CD69 and CD86 correlated with PK exposure. In CLL patients, 7 days of dosing with ACP-196 at 200 mg QD resulted in a 94% Btk target occupancy [1].

Reference:
[1] http://cancerres. aacrjournals.org/content/75/15_Supplement/2596