The rationales and inhibitor design principles will be discussed. STRUCTURE AND FUNCTIONS OF MNKS Mnk1 and Mnk2 are threonine /serine protein kinases and were originally discovered as the result of screening for substrate s or binding partners for Erk [56, 57]. pathway (Figure ?(Figure2).2). Erk1/2 and p38 then phosphorylate MAP kinase-interacting kinase 1 (Mnk1) and Mnk2. The Erk pathway is also activated in many cancers, reflecting, for example, activating mutations in Ras (found in around 20% of tumour cells) or loss of function of the Ras GTPase-activator protein NF1. Mnk1 and Mnk2 specifically phosphorylate serine 209 (Ser209) of eIF4E within the eIF4F complex, by virtue of the interaction between eIF4E and the Mnks, which serves to recruit Mnks to act on eIF4E [49, 52]. Mnk1 and Mnk2 knock-out or knock-in mice, in which Ser209 was replaced by alanine, showed no eIF4E phosphorylation and significantly attenuated tumour growth [53-55]. Significantly, while Mnk GDC-0152 activity is necessary for eIF4E-mediated oncogenic transformation, it is dispensable for normal development [53]. Pharmacologically inhibiting Mnks may, therefore, present an attractive therapeutic strategy for cancer. Despite increased understanding of structure and function of the Mnks, little progress has been made with Mnk-targeted drug discovery. In this review we intend to update the progress made in validating the Mnks as a potential therapeutic target and to provide an insight into binding models of selected prototype inhibitors in complex with the Mnks. The rationales and inhibitor design principles will be discussed. STRUCTURE AND FUNCTIONS OF MNKS Mnk1 and Mnk2 are threonine /serine protein kinases and were originally discovered as the result of GDC-0152 screening for substrate s or binding partners for Erk [56, 57]. So far four human Mnk isoforms (Mnk1a, 2a, 1b and 2b) and two mouse Mnk isoforms (Mnk1and 2) have been reported [56-60]. Sequence alignment analysis reveals that all four isoforms have a nuclear localization indication (NLS) and Rabbit Polyclonal to POU4F3 an eIF4G-binding site within GDC-0152 their N-terminal locations (Amount ?(Amount3A)3A) which, respectively, permit the kinases to enter the nucleus also to phosphorylate eIF4E efficiently. The central catalytic domains from the pairs of isoforms Mnk1a/b and Mnk2a/b are similar and carefully homologous between Mnk1 and Mnk2 protein [61]. The primary structural differences rest inside the C-terminal domains (Amount ?(Figure3B).3B). The C-terminal parts of Mnk1a and Mnk2a GDC-0152 include a MAPK-binding site, and therefore could be turned on and phosphorylated by Erk and p38 MAPK [49, 56]. Their brief GDC-0152 isoforms, 2b and Mnk1b, however, absence this domains and so are poor substrates for Erk or p38 [58-61]. At least two threonine residues (Thr209 and Thr214 in individual Mnks indicated in Fig. ?Fig.3A)3A) in this area are phosphorylated by MAPKs, and their substitute with alanine leads to inactive kinases [56, 60, 62]. The threonine residues in Mnks match the residues in MK2/3 (MAPK-activated proteins kinases), which may be phosphorylated by p38 also, suggesting an identical activation system [63]. Furthermore, Mnk1a localises towards the cytoplasm mostly, whereas a substantial percentage of the choice Mnk variations is at the nucleus present. One possible description for this is normally that, although preserving the NLS, these isoforms absence the C-terminal nuclear export series (NES) within Mnk1a, impairing their leave in the nucleus towards the cytoplasm [58, 62, 64, 65].As the activity of Mnk1a is governed by Erk and p38 MAP kinase tightly, Mnk2a shows high basal activity, and Mnk1b and Mnk2b show, respectively, quite high and low activity, which is apparently unregulated, likely reflecting their insufficient binding sites for Erk/p38 MAPK [65]. Open up in another window Amount 3 Schematic representation from the framework of splice variations of individual Mnk1 and Mnk2(A) Series position of kinase domains inserts the.