The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design?
Recent investigations in our laboratories have highlighted that the inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) is an excellent target for the development of novel anti-cancer agents. Using a combination of the known crystal structure of PP1 and the modelled structure of PP2A, we have rationally designed a new class of protein phosphatase inhibitors, cantharimides, which exhibit broad-spectrum anti-cancer activity. Synthetic modifications of the simplest known PP1 and PP2A inhibitor, norcantharidin, has led to the development of potent PP1 and PP2A inhibitors.
McCluskey
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Medicinal Chemistry Group, School of Environmental and Life Sciences, The University of Newcastle, NSW, Australia. amcclusk@mail.newcastle.edu.au
Ackland
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SP
Gardiner
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E
Walkom
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CC
Sakoff
J A
JA
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002193:Cantharidin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010749:Phosphoprotein Phosphatases; D002193:Cantharidin