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

J Med Chem. 2016 Apr 14;59(7):3063-78. doi: 10.1021/acs.jmedchem.5b01712. Epub 2016 Apr 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice, SCID
  • Molecular Targeted Therapy / methods
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • BCR-ABL1 fusion protein, human
  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • MKNK1 protein, human
  • Fusion Proteins, bcr-abl
  • MKNK2 protein, human
  • Protein Serine-Threonine Kinases