Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
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- 作者：Joseph Cherian ; Kassoum Nacro ; Zhi Ying Poh ; Samantha Guo ; Duraiswamy A. Jeyaraj ; Yun Xuan Wong ; Melvyn Ho ; Hai Yan Yang ; Joma Kanikadu Joy ; Zekui Perlyn Kwek ; Boping Liu ; John Liang Kuan Wee ; Esther HQ Ong ; Meng Ling Choong ; Anders Poulsen ; May Ann Lee ; Vishal Pendharkar ; Li Jun Ding ; Vithya Manoharan ; Yun Shan Chew ; Kanda Sangthongpitag ; Sharon Lim ; S. Tiong Ong ; Jeffrey Hill ; Thomas H. Keller
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：April 14, 2016
- 年：2016
- 卷：59
- 期：7
- 页码：3063-3078
- 全文大小：765K
- 年卷期：0
- ISSN：1520-4804
文摘
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.