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J Med Chem. 2018 May 24;61(10):4348-4369. doi: 10.1021/acs.jmedchem.7b01714. Epub 2018 May 7.

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

Author information

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.

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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