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