AZD8330

AZD8330 (ARRY-424704;ARRY-704) is a potent, selective, non-ATP competitive MEK1/2 inhibitor with IC50 of 7 nM; displays no inhibitory activity against a panel of >200 other kinases; demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK1/2 inhibitor sensitive cell lines; inhibits ERK phosphorylation and causes tumor growth inhibition in Calu-6 rat xenograft.Solid Tumors Phase 1 Discontinued(In Vitro):AZD8330 is a selective allosteric MEK1/ MEK2 inhibitor. Exposing human osteosarcoma cell lines MOS, U2OS, and 143B to a concentration of 0.5 μM of Trametinib, AZD8330 or TAK-733 for 6 hours, leads to loss of ERK phosphorylation indicating effective MEK inhibition.The activity of these three inhibitors is tested using concentration ranges in six osteosarcoma cell lines: MOS, U2OS, KPD, ZK58, 143b and Saos-2. All three inhibitors decrease viability of MOS and U2OS and strongly affect 143b. By contrast, viability of KPD, ZK58 and Saos-2 is not affected by any of the three inhibitors.(In Vivo):In tumour xenograft models, AZD8330 demonstrates dose-dependent tumour growth inhibition of approximately 90% at tolerated doses (1.0 mg/kg once daily [OD]).