similar to the other statins, but it also has similarities to rotenone and other compounds that disrupt the mitochondrial energy chain, as well as to some antibiotics and toxicants, such as n-nitrosodiethylamine. In that same vein, the comparisons show that rosuvastatin is most similar to the “core” statin signature. In some respects it is the average statin, but it also has profile matches to microtubule modulators and DNA binding compounds, which could explain some of its off-target activities.

  • Atorvastatin, or Lipitor, is very similar to the other statins, but it also matches closely both FK506 and rapamycin, both of which are immunosuppressive drugs used to prevent rejection of transplanted organs. In particular, atorvastatin has activity on the S6 kinase pathway, which is why it matches up with the two immunosuppressive compounds, suggesting that it, too, will have immunomodulatory activity. This is important information because the anti-inflammatory activity of statins is essential to how they work.

  • Finally, pravastatin’s global profile is notably different from the profiles of all the other statins. The part of its profile relating to its activity on HMG-CoA reductase is similar to that of the other statins, since all statins are inhibitors of this enzyme; over the rest of its profile, however, pravastatin is similar to cyclooxygenase inhibitors, indicating that it may have unique anti-inflammatory properties. This is a testable hypothesis, one that is supported by the literature.

A global profile of cholesterol was also run to identify drugs with similar profiles. A number of hits were returned, including rotenone, β-laphachone, Ketek, and nefazodone. All of these compounds exhibit some toxicity, and all can be toxic to hepatocytes. Because high levels of cholesterol are also toxic to hepatocytes, these results make sense. Although this profile would not necessarily disqualify Ketek from consideration, it would prompt researchers to investigate further its effects on hepatocytes in vitro and in vivo.

SUMMARY

The profiles generated by this technology can offer a number of insights into the potential toxicity of compounds, as well as into desirable drug mechanisms. BioSeek is working to develop a comprehensive BioMAP database connecting drug biology to clinical responses. Odyssey Thera’s current strategy is to rigorously define training sets based on toxicants as well as desirable drug classes and then to match test compounds to these profiles. In this way, the researchers hope to be able to enable a deeper understanding of cellular networks and drug targets and to facilitate more informed discovery and development decisions.



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