Abstract #3696: AZD8330 (ARRY-424704): Preclinical evaluation of a potent, selective MEK 1/2 inhibitor currently in phase I trials

The dual-specificity kinases MEK 1/2 play key roles in tumorgenesis by activating the serine/threonine kinases ERK 1/2. These kinases play critical roles in cellular proliferation, differentiation, apoptosis, migration, and invasion. As such, inhibition of MEK 1/2 is an attractive mechanism for anti-cancer therapy and several small molecule inhibitors have entered human clinical trials, including AZD6244 (ARRY-142886). We have discovered AZD8330 (ARRY-424704), a novel, selective, highly efficacious, uncompetitive MEK 1/2 inhibitor with superior drug-like properties. In cell-free kinase assays, AZD8330 inhibits MEK with an IC 50 of 7 nM, and has no inhibitory activity against over 200 other kinases at concentrations up to 10 \#956;M. AZD8330 demonstrates sub-nano molar potency in mechanistic (pERK) and low to sub-nano-molar potency in functional (proliferation) assays in MEK inhibitor sensitive cell lines. In a Calu-6 rat xenograft PK/PD model a single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by > 90% for between 4 and 8 hours. In pharmacokinetic studies, the high permeability, low predicted hepatic Cl and solubility of AZD8330 translates to high %F and long plasma half-life in rat and dog , 63 and 77% and 10 and 11 hours, respectively following oral administration. The pharmacodynamic and pharmacokinetic properties of AZD8330 result in impressive efficacy at low doses in rodent models of cancer. Doses as low as 0.4 mg/kg once daily are sufficient for > 80% tumour growth inhibition in the Calu-6 nude rat xenograft model. Comparison of once and twice daily dosing schedules indicate similar efficacy for both. In multiple-dose toxicity studies, oral dosing of AZD8330 has an acceptable overall safety profile in the rat and the dog. AZD8330 is currently in Phase I clinical trials for the treatment of cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3696.