Characterisation of fragments binding to the translation initiation factor eIF4E

Summary

Eukaryotic translation initiation factor 4E (eIF-4E) is a key component of the m7G-cap-binding protein complex eIF-4F and is required for capdependent
translation initiation. Activity of the eIF4F complex is tightly controlled by both the PI3K/Akt/mTOR and Raf/Mek/ERK pathways,
via mTOR phosphorylation of the eIF4E sequestering proteins 4E-BP1-3 and phosphorylation of eIF4E by MNK1/2, downstream of ERK. EIF4E
is therefore a key node downstream of pathways that are frequently dysregulated in cancer.
Formation of the eIF4F complex leads to translation of ‘weak’ mRNAs, encoding key cell growth and survival proteins such as cyclin D1,
c-MYC and Mcl1, supporting cancer cell proliferation, and has been associated with resistance to MAPK and PI3K inhibitors1,2. Identification
of an inhibitor of eIF4E would therefore be of therapeutic value.
The Astex fragment screening platform was used to identify fragment hits binding to an unprecedented binding site on eIF4E. These weak
hits were optimised using structure guided design into functional effects on cap dependent translation by inhibiting the formation of eIF4F translation initiation complex.

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