|Discovery Of Mnk Kinase Inhibitors as Anticancer Agents|
Kassoum Nacro1, Haiyan Yang1, Melvyn Ho1, Joseph Cherian1, Samantha Guo1, Po Zhi Ying1,Thomas Keller1, CongBao Kang1, Young Mee Kim1, Shovanlal Gayen1, Qiwe Huang1, Angela Chen1, Joma Kanikadu Joy1, Thuy Thi Hanh Nguyen1, Boping Liu1, Esther Ong1, Jeffrey Hill1, Jacklyn Yong1, Choong Meng Ling1, Lee May Ann1, Kanda Sangthongpitag1, Vishal Pendharkar1, Tai Shi Jing1, Saha Sudipta1, Tiong Sin Ong2, Sharon Lim2, Ralf Jauch3, Christopher Brown4
1. Experimental Therapeutics Centre, A*STAR, 31 Biopolis Way, #3-01, Singapore 138669
The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in several types of human cancers and is associated with cellular transformation, tumorigenesis, and metastatic progression. eIF4E has also been linked to poor prognosis in patients with solid tumors. Mitogenactivated protein kinase-interacting kinases 1 and 2 (Mnk1 and Mnk2) are downstream effectors of mitogen-activated protein kinase pathways and phosphorylate eIF4E on serine 209. This phosphorylation has been reported to be required for eIF4E oncogenic activity.
Knock-in mice, in which the eIF4E serine 209 was mutated to alanine, are resistant to oncogeneinduced transformation and to Pten loss-induced prostate cancer (1). Phosphorylation of eIF4E is completely abolished in Mnk1 and Mnk2 double knock-out mice which are either resistant to transformation or significantly retard tumor formation (2). Mnk DKO mice and eIF4ES209A mice are viable with no apparent abnormalities or defects.
These data suggest that inhibitors of Mnk1 and Mnk2 may be effective anticancer drugs and are likely to have minimal side effects.
Our aim is to develop Mnk 1&2 inhibitors with the following attributes:
Fragment-based Drug Discovery
Fragments from literature (3) with good ligand efficiency (LE) could be the starting point to design and synthesize potent Mnk inhibitors.
LE measures the binding energy per atom.
Binding and cell-based assays
Pharmacokinetics of Lead Molecule ETC-1780445
1. Luc Furic et al PNAS 2010, 107 (32), 14134-14139.
We would like to thank A*STAR Biomedical Research Council for financial support.