Sapitinib

Sapitinib (AZD-8931, AZD8931) is a equipotent, reversible inhibitor of EGFR, ErbB2 and ErbB3 with IC50 of 4. 3 and 4 nM (phosphorylation inhibition), respectively; displays >1,000-fold selectivity over a panel of 206 of kinases, >100-fold selectivity for MNK1 and Flt3; AZD8931 is significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines; inhibits xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.Colon Cancer Phase 2 Clinical (In Vitro) :AZD8931 shows potent inhibitory effect on erbB2 in the ligand-independent MCF-7 cl24 cells, with IC50 of 59 nM. AZD8931 (1 μM) has no significant effect on EGFR expression level, but significantly inhibitsphosphorylation of Akt in a time- and dose-dependent manner in both SUM149 and FC-IBC-02 cells. AZD8931 (0.01, 0.1, 1, or 2 μM) inhibits proliferation and induces apoptosis in human IBC cells. At the cellular level, AZD8931 inhibits EGF-stimulated phosphorylation of EGFR in the KB cell line (IC50: 4 nM) and heregulin-stimulated phosphorylation of HER2 (IC50: 3 nM) and HER3 (IC50: 4 nM) in the MCF-7 cell line. However, AZD8931 exhibits no CYP P450 inhibition (IC50 > 10 μM against 1A2, 2C9, 2C19, 2D6, and 3A4) . (In Vivo) :AZD8931 (6.25-50 mg/kg, p.o.) significantly inhibits BT474c (breast), Calu-3 (NSCLC), LoVo (colorectal), FaDu (SCCHN), and PC-9 (NSCLC) tumor xenograft growth. AZD8931 is active in xenograft tumor models responsive to EGFR inhibition alone (LoVo and PC-9) or EGFR or erbB2 inhibition (BT474c, Calu-3, and FaDu) . AZD8931 causes pharmacodynamic changes in proliferation and apoptosis markers in human tumor xenograft models. AZD8931 (25 mg/kg, p.o.) significantly inhibits the growth of SUM149 and FC-IBC-02 cells in vivo in SCID mice. AZD8931 displays favorable oral pharmacokinetics in rat and dog (low clearance and good bioavailability) and low human hepatocyte turnover (Clint < 4.5 μL/min/106 cells) . In nude mouse after oral administration at 50 mg/kg, AZD8931 shows improved exposure, and at at 100 mg/kg oral dose once daily, it shows potent tumor growth inhibition activity in the LoVo mouse xenograft model.