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
- Experimental Therapeutics Centre, A*STAR, 31 Biopolis Way, #3-01, Singapore 138669
- Cancer and stem cell biology Program, Duke-NUS Graduate Medical School, 8 College road, Singapore 169857
- Genome Institute of Singapore, A*STAR, 60 Biopolis Street #02-01Genome, Singapore 138672
- p53 Laboratory, A*STAR, 8A Biomedical Grove, #06-06, Immunos, Singapore 138648
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:
- in vitro IC50 < 50 nM
- Bioavailability > 30%
- Cyp 3A4, 2D6 IC50 > 10 μM
- hERG IC50 > 10 μM
Lead Finding Strategy
- Fragments screening
- Cross validate binding by at least two biophysical techniques
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.
Potent ligand such as ETC-1693110 and ETC-1693112 increase Mnk2 thermal unfolding by 23°C!
Binding and cell-based assays
Pharmacokinetics of Lead Molecule ETC-1780445
- Luc Furic et al PNAS 2010, 107 (32), 14134-14139.
- Takeshi Ueda et al PNAS 2010, 107 (32), 13894-13990
- Julen Oyarzabal et al J. Med. Chem., 2010, 53 (18), pp 6618–6628
We would like to thank A*STAR Biomedical Research Council for financial support.
- ETC-1780445-2 is a potent Mnk 1/2 inhibitor, that demonstrates high selectivity against other kinases
- ETC-1780445-2 shows excellent drug like properties
- Access to proprietary compounds with divers kinase selectivity profile to should allow us to fully assess the benefits of Mnk1/2 inhibitors.