RT Journal Article
SR Electronic
T1 Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 935
OP 948
DO 10.1124/mol.115.100131
VO 88
IS 5
A1 Sunita K.C. Basnet
A1 Sarah Diab
A1 Raffaella Schmid
A1 Mingfeng Yu
A1 Yuchao Yang
A1 Todd Alexander Gillam
A1 Theodosia Teo
A1 Peng Li
A1 Tom Peat
A1 Hugo Albrecht
A1 Shudong Wang
YR 2015
UL http://molpharm.aspetjournals.org/content/88/5/935.abstract
AB Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-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 nontoxic 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 a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. 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 antiproliferative 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 anticancer therapeutics.