Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 & 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 & 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
Title:
Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 & 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
Other Titles:
Journal of Medicinal Chemistry
Publication Date:
24 March 2016
Citation:
Abstract:
Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia (CML) do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 & 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 & 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial SAR studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 & 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eIF4E in the tumor tissues. Kinase selectivity of these compounds is also presented.
License type:
PublisherCopyrights
Funding Info:
Biomedical Sciences Institutes (BMSI) and Joint Council Office (JCO Project 11 03 FG 07 05), Agency for Science, Technology and Research (A*STAR), Singapore. National Medical Research Council, Ministry of Health, Singapore.
Description:
Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 & 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
ISSN:
0022-2623
1520-4804
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