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.
Joseph Cherian  1 ,  Kassoum Nacro  1 ,  Zhi Ying Poh  1 ,  Samantha Guo  1 ,  Duraiswamy A Jeyaraj  1 ,  Yun Xuan Wong  1 ,  Melvyn Ho  1 ,  Hai Yan Yang  1 ,  Joma Kanikadu Joy  1 ,  Zekui Perlyn Kwek  1 ,  Boping Liu  1 ,  John Liang Kuan Wee  1 ,  Esther H Q Ong  1 ,  Meng Ling Choong  1 ,  Anders Poulsen  1 ,  May Ann Lee  1 ,  Vishal Pendharkar  1 ,  Li Jun Ding  1 ,  Vithya Manoharan  1 ,  Yun Shan Chew  1 ,  Kanda Sangthongpitag  1 ,  Sharon Lim  2 ,  S Tiong Ong  2 ,  Jeffrey Hill  1 ,  Thomas H Keller  1
Affiliations
  • 1. Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
  • 2. Duke-National University of Singapore (NUS) Graduate Medical School , 8 College Road, Singapore, Singapore 169857.
PMID: 27011159 DOI: 10.1021/acs.jmedchem.5b01712
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.