A New Compound with Increased Antitumor Activity by Cotargeting MEK and Pim-1
Yanan Li,
Ying Cheng,
Maoqi Zhang,
Xiaoli He,
Li Kong,
Kexiang Zhou,
Yunfu Zhou,
Lin Li,
Hongqi Tian,
Xiaomin Song,
Yukun Cui
Affiliations
Yanan Li
College of Medical Imaging, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
Ying Cheng
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, Tianjin 300192, China
Maoqi Zhang
Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
Xiaoli He
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Li Kong
Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
Kexiang Zhou
Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China
Yunfu Zhou
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Lin Li
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
Hongqi Tian
Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 238 Baidi Road, Tianjin 300192, China; Corresponding author
Xiaomin Song
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Corresponding author
Yukun Cui
Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou University Medical College Cancer Hospital, 7 Raoping Road, Shantou, Guangdong 515031, China; Corresponding author
Summary: 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.
