1. Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2
- Author
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Jacek Kwiatkowski, Boping Liu, Shermaine Pang, Nur Huda Binte Ahmad, Gang Wang, Anders Poulsen, Haiyan Yang, Yong Rui Poh, Doris Hui Ying Tee, Esther Ong, Priya Retna, Nurul Dinie, Perlyn Kwek, John Liang Kuan Wee, Vithya Manoharan, Choon Bing Low, Peck Gee Seah, Vishal Pendharkar, Kanda Sangthongpitag, Joma Joy, Nithya Baburajendran, Anna Elisabet Jansson, Kassoum Nacro, Jeffrey Hill, Thomas H. Keller, and Alvin W. Hung
- Subjects
Models, Molecular ,Structure-Activity Relationship ,Eukaryotic Initiation Factor-4E ,Cell Line, Tumor ,Drug Discovery ,Intracellular Signaling Peptides and Proteins ,Molecular Medicine ,Humans ,Phosphorylation ,Protein Serine-Threonine Kinases ,Crystallography, X-Ray ,Protein Kinase Inhibitors - Abstract
Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.
- Published
- 2020