Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

  • J Med Chem. 2018 May 24;61(10):4348-4369. doi: 10.1021/acs.jmedchem.7b01714.
Haiyan Yang  1 ,  Lohitha Rao Chennamaneni  2 ,  Melvyn Wai Tuck Ho  1 ,  Shi Hua Ang  1 ,  Eldwin Sum Wai Tan  1 ,  Duraiswamy Athisayamani Jeyaraj  1 ,  Yoon Sheng Yeap  1 ,  Boping Liu  1 ,  Esther Hq Ong  1 ,  Joma Kanikadu Joy  1 ,  John Liang Kuan Wee  1 ,  Perlyn Kwek  1 ,  Priya Retna  1 ,  Nurul Dinie  1 ,  Thuy Thi Hanh Nguyen  1 ,  Shi Jing Tai  1 ,  Vithya Manoharan  1 ,  Vishal Pendharkar  1 ,  Choon Bing Low  1 ,  Yun Shan Chew  1 ,  Susmitha Vuddagiri  1 ,  Kanda Sangthongpitag  1 ,  Meng Ling Choong  1 ,  May Ann Lee  1 ,  Srinivasaraghavan Kannan  3 ,  Chandra S Verma  3  4  5 ,  Anders Poulsen  1 ,  Sharon Lim  6 ,  Charles Chuah  6 ,  Tiong Sin Ong  6  7 ,  Jeffrey Hill  1 ,  Alex Matter  1 ,  Kassoum Nacro  1
Affiliations
  • 1. Experimental Therapeutics Centre (ETC) , A*STAR , 31 Biopolis Way, Nanos #03-01 , 138669 Singapore.
  • 2. Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES), A*STAR , 8 Biomedical Grove, Neuros, #07-01 , 138665 Singapore.
  • 3. Bioinformatics Institute (BII) , A*STAR , 30 Biopolis Street, #07-01 Matrix , 138671 Singapore.
  • 4. School of Biological Sciences , Nanyang Technological University , 60 Nanyang Drive , 637551 Singapore.
  • 5. Department of Biological Sciences , National University of Singapore , 14 Science Drive 4 , 117543 Singapore.
  • 6. Duke-NUS Medical School , 8 College Road , 169857 Singapore.
  • 7. Department of Medicine , Duke University Medical Center , Durham , North Carolina 27710 , United States.
PMID: 29683667 DOI: 10.1021/acs.jmedchem.7b01714
Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.

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