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New NSAIDs derivatives for cancer treatment - Protective and less toxic, targeting PPAR gamma
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely-used anti-inflammatory and anti-pyretic therapeutic agents to treat human diseases. However, long-term use of NSAIDs comes with risks. Many NSAIDs are COX-1 inhibitors, which are associated with significant GI toxicities. The Marnett Lab at Vanderbilt University has developed new derivatives of NSAIDs that retain their protective effects but do not cause debilitating and potentially fatal toxicities.
COX inhibitors are well profiled compounds in humans, with well-defined pharmacokinetics. Early COX inhibitors had rich pharmacology, acting at many receptors. The Marnett laboratory has used these well characterized scaffolds to isolate individual actions of the original COX inhibitors.
One such discovery is indoleacetic acid and indenacetic acid derivatives with reduced gastrointestinal toxicity (reduced cyclooxygenase inhibiting activity), but which can still be protective by interacting with other polypeptides, such as peroxisome proliferators-activated receptor (PPARs, particularly PPARγ) and γ-secretase. PPARs have been associated with pathological conditions such as atherosclerosis, inflammation, obesity, diabetes, the immune response, and ageing. Activation of PPARγ can cause anti-proliferation, apoptosis, differentiation, and anti-inflammatory responses in certain types of cancer cells.
Moreover, prostate cancer is the second most common cancer in men, with 160,000 new cases annually in the US. 20% of all cases develop into castrate-resistant prostate cancer (CRPC) and are always fatal. The Marnett Lab has made indomethacin analogs as a treatment method, by inhibiting a biological activity of a human aldo-keto reductase family 1, member C3 (AKR1C3) polypeptide, but not inhibiting the COX targets of NSAIDs as indomethacin itself.
• Reduced gastrointestinal toxicity
• PPARγ subtype selective activation
• Well characterized SAR
• Parent scaffold was well profiled in humans
Patents and further reading
US patents: 7,491,744; 8,168,656; 13/461,236; 61/548,004 and additional patents in other countries. For additional reading on the imaging agents, see this J. Med Chem publication (2008, 51;16, 4911-9)
Inventors:Lawrence MarnettAndrew FeltsJeffrey PrusakiewiczChuan Ji