Characterisation of fragments binding to the translation initiation factor eIF4E

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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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Characterisation of fragments binding to the translation initiation factor eIF4E

Fragment Based Drug Discovery: An Organic Synthesis Perspective

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Summary

  •  Fragment hits bind with high energy interactions, so have high ligand efficiency (LE).
  • Small libraries of fragments can sample chemical space more widely There are estimated to be ~ 1050 compounds < 500 MW, cf.
    ~106 fragments < 250 MW.
  • Potencies in mM rather than μM range require sensitive biophysical techniques to detect interactions, e.g. X-Ray, NMR, SPR, ITC.
  • Millimolar fragments can be converted to nanomolar leads with the  support of structure based drug design.

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Fragment Based Drug Discovery: An Organic Synthesis Perspective

TAT: Anti-Angiogenic Activity of Fragment-Derived Inhibitors of METAP2

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Summary

Methionine amino peptidase (MetAP) 2 is the target of the anti- angiogenic natural product fumagillin and so is believed to play a role in angiogenesis. MetAPs are metalloenzymes which cleave the N- terminal methionine from newly formed polypeptides. This allows essential post-translational modifications, such as myristoylation and acetylation, to take place thus generating fully functional proteins.
Analogues of fumagillin have shown activity in several different disease models, where angiogenesis may be relevant, including
oncology. Semi-synthetic analogues of fumagillin, such as TNP-470, have shown evidence of antitumor activity in the clinic but poor pharmacokinetic properties and neurotoxic effects have limited their development. Nevertheless MetAP2 remains a promising oncology
target and inhibitors with improved properties should have potential as anti-angiogenic agents.
We have screened MetAP2 using our fragment-based screening approach (Pyramid™) and identified multiple low molecular weight fragments, which bind at the active site of MetAP2 in diverse ways. Three of these were optimised to novel hit series using structure- based drug design and their anti-angiogenic properties are described here.

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TAT: Anti-Angiogenic Activity of Fragment-Derived Inhibitors of METAP2