UNASSIGNED: Elevated levels of phosphorylated @entity4043 ( @entity4043 ) have been implicated in many @entity5 types, and mitogen activated protein kinase (MAPK)-interacting kinases (Mnks) are the only known kinases that phosphorylate @entity4043 at Ser209. The phosphorylation of @entity4043 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 @entity5 therapy. However, a lack of specific @entity34001 inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of novel series of @entity34001 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 @entity23815 and @entity34002 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 @entity23815 and @entity34002 activities, and demonstrated potent anti-proliferative properties against the @entity1 @entity3052 cell line. Interestingly, @entity855 -/substrate-competitive inhibitors were found to be highly selective for @entity34002 with little or no activity for @entity23815 . Our study suggests that @entity23815 and @entity34002 share a common structure of the allosteric inhibitory binding site, but possess different structural features of the @entity855 catalytic domain. The findings will assist in the future design and development of @entity34001 targeted anti- @entity5 therapeutics.

Identification of a Highly Conserved Allosteric Binding Site on XXXX and @entity34002 .

@entity1 :: ('9606', 'Species') :: ['MV4-11'] @entity34001 :: ('538', 'Gene') :: ['Mnk'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer'] @entity23815 :: ('8569', 'Gene') :: ['Mnk1'] @entity3052 :: ('MESH:D015470', 'Disease') :: ['acute myeloid leukemia'] @entity34002 :: ('2872', 'Gene') :: ['Mnk2'] @entity4043 :: ('1977', 'Gene') :: ['eIF4E', 'eukaryotic initiation factor 4E'] @entity855 :: ('MESH:D000255', 'Chemical') :: ['ATP']
@entity23815 :: (8569,Gene) :: ['Mnk1']
