2018 AACR: Development of a potent class of small molecule inhibitors of the MDM2-p53 protein-protein interaction

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Summary
In response to cellular stress, the p53 tumor suppressor is activated to modulate cell cycle progression, DNA repair, and cell death. The activity of p53 is tightly regulated by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. Inhibition of the MDM2-p53 interaction in tumors carrying wild-type p53 can therefore reactivate p53 and elicit an anti-cancer effect. Small molecule inhibitors of the MDM2-p53 interaction remains a promising strategy for cancer therapy and a number of these compounds are in clinical development.

An isoindolinone series, identified by the Northern Institute for Cancer Research (NICR), has been used as a starting point for the development of potent MDM2-p53 inhibitors. Structure based drug design was applied during lead optimisation to gain potency whilst also focusing on stabilizing the main metabolically labile position and reducing lipophilicity.  This approach led to potent compounds with EC50 <1 nM against MDM2 in cell-free ELISA assays and EC50 <30 nM for p53 induction in SJSA-1 osteosarcoma cells. Further analyses of the compounds demonstrated an increase in the levels of p53 and p53 transcriptional targets as a result of inhibiting the MDM2-p53 interaction. Using three pairs of isogenic cell lines, the compounds were shown to be specific for cell lines with wild-type p53. Key compounds were also characterized in pharmacokinetic and pharmacodynamic studies in mice bearing the SJSA-1 tumor xenograft where they displayed strong induction of p53, 3 hours post oral administration, together with an increase in the expression of p53 target genes p21 and MDM2. These potent MDM2-p53 inhibitors have also shown significant in vivo efficacy in the SJSA-1 xenograft model at well tolerated oral doses.  Thus, promising lead compounds were identified, meriting further optimization of the series.

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Development of a potent class of small molecule inhibitors of the MDM2-p53 protein-protein interaction

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