Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells.
Journal Article (Journal Article)
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.
- Cherian, J; Nacro, K; Poh, ZY; Guo, S; Jeyaraj, DA; Wong, YX; Ho, M; Yang, HY; Joy, JK; Kwek, ZP; Liu, B; Wee, JLK; Ong, EHQ; Choong, ML; Poulsen, A; Lee, MA; Pendharkar, V; Ding, LJ; Manoharan, V; Chew, YS; Sangthongpitag, K; Lim, S; Ong, ST; Hill, J; Keller, TH
- April 14, 2016
Volume / Issue
- 59 / 7
Start / End Page
- 3063 - 3078
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States