Feedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.

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