The kinase pathway comprising Ras/Raf/MEK and ERK is one of the major pathways transmitting signals from growth factor receptors at the cell surface and is activated in many human tumors. In human malignancies, activated Ras mutations are relatively common, having been identified in about 30% of solid tumor cancers including colon, pancreatic, lung, ovarian and bladder. Similarly, activating B-Raf mutations occur in 66% of malignant melanomas. Although mutations in MEK1/2 have not been identified in human cancers, MEK is a critical member of converging kinase pathways that signal via Ras. In addition, the only known catalytic substrate for MEK is ERK, making MEK a target of interest for the development of cancer therapeutics. AS703026, a novel, potent and selective allosteric inhibitor of MEK was tested in vivo to determine pharmacokinetic (PK) characteristics, maximum tolerated dose (MTD) in mice, and efficacy of inhibition of tumor growth and pERK in mouse xenograft models of human cancer. The PK profile of AS703026 was acceptable in mice and rats, with relatively high oral bioavailability (52-57%), medium or high clearance (0.9-2.6 L/h/kg) and medium or long half-life (2.2-4.7 h). The compound was relatively well-tolerated in mice, with a 2-week MTD of 60 mg/kg BID. In cancer xenograft studies in mice, AS703026 showed remarkable activity in the human melanoma A375, the pancreatic MiaPaCa-2 and colorectal Colo-205 xenograft models, producing tumor regression at doses as low as 10 mg/kg BID orally. Although regressed A375 melanoma xenograft tumors regrew after cessation of treatment with AS703026, regressed MiaPaCa-2 tumors showed limited post-treatment regrowth. Inhibition of ERK phosphorylation in tumor and PMA-activated PBMCs from mice treated with a single oral administration of AS703026 was reduced in a manner that was proportional to plasma concentrations of the compound and was associated with apoptosis in tumor tissue, with treatment at 50 mg/kg inhibiting the target by 70-80% for up to 4 h in blood and 24 h in tumor. Preclinical in vivo results with AS703026 for PK, target inhibition and efficacy were relatively favorable overall. AS703026 is currently being tested in patients in Phase I clinical oncology trials.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3694.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO