Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2.
Jacek KwiatkowskiBoping LiuShermaine PangNur Huda Binte AhmadGang WangAnders PoulsenHaiyan YangYong Rui PohDoris Hui Ying TeeEsther OngPriya RetnaNurul DiniePerlyn KwekJohn Liang Kuan WeeVithya ManoharanChoon Bing LowPeck Gee SeahVishal PendharkarKanda SangthongpitagJoma JoyNithya BaburajendranAnna Elisabet JanssonKassoum NacroJeffrey HillThomas H KellerAlvin W HungPublished in: Journal of medicinal chemistry (2020)
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.