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The mitogen-activated protein kinases, MEK1 and 2, are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the Ras-Raf-MEK-ERK pathway and are often upregulated in a variety of cancer cell types. AS-703026 is an orally bioavailable small molecule that selectively binds to and inhibits MEK1/2, preventing the activation of downstream effector proteins and transcription factors. It potently inhibits growth and survival of human INA-6 multiple myeloma cells and cytokine-induced osteoclast differentiation with IC50 values of 10 and 18.2 nM, respectively. In mice bearing H929 MM xenograft tumors, 30 mg/kg AS-703026 reduced tumor growth significantly, which correlated with downregulated ERK1/2 activity, induced PARP cleavage, and decreased microvessels in vivo. At 10 μM, AS-703026 supressed proliferation and transformation of K-Ras mutated colorectal cancer cells resistant to EGFR antibody therapy.