title: Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells.
abstract: 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.
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cherian
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Nacro
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Zhi Ying
authors.initials: ZY
authors.lastname: Poh
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Samantha
authors.initials: S
authors.lastname: Guo
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Duraiswamy A
authors.initials: DA
authors.lastname: Jeyaraj
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Yun Xuan
authors.initials: YX
authors.lastname: Wong
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Melvyn
authors.initials: M
authors.lastname: Ho
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Hai Yan
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Joma Kanikadu
authors.initials: JK
authors.lastname: Joy
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Zekui Perlyn
authors.initials: ZP
authors.lastname: Kwek
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: John Liang Kuan
authors.initials: JL
authors.lastname: Wee
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Esther H Q
authors.initials: EH
authors.lastname: Ong
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Meng Ling
authors.initials: ML
authors.lastname: Choong
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Li Jun
authors.initials: LJ
authors.lastname: Ding
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Vithya
authors.initials: V
authors.lastname: Manoharan
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Yun Shan
authors.initials: YS
authors.lastname: Chew
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.affiliation: Duke-National University of Singapore (NUS) Graduate Medical School , 8 College Road, Singapore, Singapore 169857.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.affiliation: Duke-National University of Singapore (NUS) Graduate Medical School , 8 College Road, Singapore, Singapore 169857.
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.affiliation: Experimental Therapeutics Centre , 13 Biopolis Way, Nanos, Singapore 138669.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C491395:MKNK1 protein, human; D016044:Fusion Proteins, bcr-abl; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases