PT - JOURNAL ARTICLE AU - Sunita K C Basnet AU - Sarah Diab AU - Raffaella Schmid AU - Mingfeng Yu AU - Yuchao Yang AU - Todd A Gillam AU - Theodosia Teo AU - Peng Li AU - Tom Peat AU - Hugo Albrecht AU - Shudong Wang TI - Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2 AID - 10.1124/mol.115.100131 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.115.100131 4099 - http://molpharm.aspetjournals.org/content/early/2015/08/11/mol.115.100131.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/08/11/mol.115.100131.full AB - Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase (MAPK)-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation, but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a non-toxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II antagonists. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities, and demonstrated potent anti-proliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/substrate-competitive inhibitors were found to be highly selective for Mnk2 with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site, but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anti-cancer therapeutics.