Amin et al.. “1H, 15N and 13C backbone assignments of GDP-bound human H-Ras mutant G12V.” Springer Link. 15 September 2015. DOI: 10.1007/s12104-015-9649-4

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Summary

Harvey Ras (H-Ras) is a membrane-associated GTPase with critical functions in cell proliferation and differentiation. The G12V mutant of H-Ras is one of the most commonly encountered oncoproteins in human cancer. This mutation disrupts the GTPase activity of H-Ras, leading to constitutive activation and aberrant downstream signalling. Here we report the backbone resonance assignments of human H-Ras mutant G12V lacking the C-terminal membrane attachment domain.

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Amin et al.. “1H, 15N and 13C backbone assignments of GDP-bound human H-Ras mutant G12V.” Springer Link. 15 September 2015. DOI: 10.1007/s12104-015-9649-4

Woolford et al. “Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.” J Med Chem, 27 May 2016

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Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

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Woolford et al. “Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.” J Med Chem, 27 May 2016. DOI: 10.1021/acs.jmedchem.6b00212

Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783

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Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783

Davies et al. “Mono-acidic inhibitors of the KEAP1 Kelch-NRF2 protein-protein interaction with high cell potency identified by Fragment-based Discovery.” J Med Chem, 31 March 2016

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KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch–NRF2 interaction. X-ray crystallographic screening identified three distinct “hot-spots” for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1–NRF2 interaction.

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Davies et al. “Mono-acidic inhibitors of the KEAP1 Kelch-NRF2 protein-protein interaction with high cell potency identified by Fragment-based Discovery.” J Med Chem, 31 March 2016. DOI: 10.1021/acs.jmedchem.6b00228

Palmer et al. “Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD) .” Org. Biomol. Chem., 2016,14, 1599-1610

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This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1–3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment- to-lead elaboration.

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Palmer et al. “Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD).” Org. Biomol. Chem., 2016,14, 1599-1610; PDF, 608 kB

Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783 .

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What’s a good fragment? Fragment-based drug discovery is well-established within many pharmaceutical, biotech, and academic institutions for generating new drugs. In this Essay, the opportunities and challenges for organic chemists to design and synthesize new fragments are described.

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Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783 .

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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  •  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