Mechanism of action: Class I PI3K isoforms, PI3Kinase α and PI3Kinase δ

Preclinical pharmacology

AZD8835 is a selective, oral inhibitor of PI3K isoforms α and δ with the following activity in enzymatic assays: PI3K α – IC50 = 6nM (equipotent vs wt and E545K / H1047R mutants); PI3K δ – IC50 = 6nM; PI3K γ – IC50 = 90nM; PI3K β – IC50 = 431nM. Inhibition of signalling in cells (pAKT endpoint): PI3K α – IC50 = 57nM; PI3K δ – IC50 = 49nM; PI3K β – IC50 = 3.6μM; PI3K γ - IC50 = 532nM.

Inhibition of tumour cell line proliferation: GI50 <1μM in sensitive lines (many carry PIK3CA mutation and/or Her 2 amplification, e.g. HCC1187, T47D, MDA-MB-453, MCF7).

Inhibition of signalling in MCF7 human xenograft in mice (pAKT endpoint): >90% 1 hour after administration of 25mg/kg. The compound demonstrated complete tumour growth inhibition @ 25mg/kg continuous dosing, twice daily, orally, in MCF7 xenograft model (human xenograft tumour growth model in mice). Additional data covering a range of models, doses and dosing schedules is available on request.