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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

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Johnson et al. “Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase.” ACS Medicinal Chemistry Letters, DOI:10.1021/ml5001245

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Howard et al. “Fragment-Based Discovery of 6-Azaindazoles As Inhibitors of Bacterial DNA Ligase.” ACS Medicinal Chemistry Letters (2013). DOI: 10.1021/ml4003277 .

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Jhoti et al.. “The ‘rule of three’ for fragment-based drug discovery: where are we now?.” Nature Reviews Drug Discovery (2013). DOI: DOI:10.1038/nrd3926-c1 .

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Crawford et al.. “SAHA abrogates FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma.” Cell Death Dis. 2013 Jul; 4(7): e733 .

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Chaneton, et al. “Serine is a natural ligand and allosteric activator of pyruvate kinase M2.” Nature 2012. DOI: 10.1038/nature11540.

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Saalau-Bethell, et al. “Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.” Nature Chemical Biology 2012. DOI: 10.1038/NCHEMBIO.1081.

Thomas G. Davies and Ian J. Tickle. “Fragment Screening Using X-Ray Crystallography.” Topics in Current Chemistry 317 2012: 33-59. DOI: 10.1007/128_2011_179.

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Thomas G. Davies and Ian J. Tickle. “Fragment Screening Using X-Ray Crystallography.” Topics in Current Chemistry 317 2012: 33-59. DOI: 10.1007/128_2011_179.