1613167-93-3Relevant academic research and scientific papers
Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
Cherian, Joseph,Nacro, Kassoum,Poh, Zhi Ying,Guo, Samantha,Jeyaraj, Duraiswamy A.,Wong, Yun Xuan,Ho, Melvyn,Yang, Hai Yan,Joy, Joma Kanikadu,Kwek, Zekui Perlyn,Liu, Boping,Wee, John Liang Kuan,Ong, Esther Hq,Choong, Meng Ling,Poulsen, Anders,Lee, May Ann,Pendharkar, Vishal,Ding, Li Jun,Manoharan, Vithya,Chew, Yun Shan,Sangthongpitag, Kanda,Lim, Sharon,Ong, S. Tiong,Hill, Jeffrey,Keller, Thomas H.
, p. 3063 - 3078 (2016/05/19)
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.
COMPOUNDS INCLUDING MAP KINASE INTERACTING KINASES 1 AND 2 (MNK1 AND MNK2) MODULATORS AND ABL AND ABL (T315I) INHIBITORS, AND USES THEREOF
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Paragraph 000233; 000234; 000254, (2014/06/24)
The present invention relates to certain piperazine-based compounds that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b and/or as ABL or ABL (T315I) inhibitors. The invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of cancer, inflammatory and Alzheimer disease conditions, as well as methods of treatment of these disorders.
