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

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.