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

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

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.

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