期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 7, 页码 3063-3078出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01712
关键词
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资金
- Biomedical Sciences Institutes (BMSI)
- Joint Council Office (JCO), Agency for Science, Technology, and Research (A*STAR), Singapore [11 03 FG 07 05]
- Clinician Scientist Award by National Medical Research Council, Ministry of Health, Singapore
Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.
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