nvp-ast487 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Chemistry Techniques, Synthetic; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Female; Fusion Proteins, bcr-abl; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice, SCID; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Structure-Activity Relationship; Xenograft Model Antitumor Assays