New Insights into Nelfinavir's Anti-Cancer Properties

Researchers at the University of California have shed light on the molecular mechanisms underlying the anti-cancer effects of Nelfinavir, a potent HIV-protease inhibitor. Using a novel computational approach, the team identified multiple protein kinase-like superfamily members as putative off-targets of Nelfinavir, which are involved in regulating cellular processes crucial for carcinogenesis and metastasis. The findings, published in Plos Computational Biology, provide a molecular basis for the broad-spectrum anti-cancer effect of Nelfinavir and suggest opportunities for optimizing the drug as a targeted polypharmacology agent.

Key Takeaways:

• Nelfinavir, a potent HIV-protease inhibitor, exhibits pleiotropic effects in cancer cells, including the suppression of the Akt signaling pathway.
• A structural proteome-wide off-target pipeline was used to identify putative human off-targets of Nelfinavir, which were found to be involved in regulating cellular processes vital for carcinogenesis and metastasis.
• The computational predictions were supported by kinase activity assays and are consistent with existing experimental and clinical evidence.
• The researchers concluded that the finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir.
• The study suggests opportunities to optimize the drug as a targeted polypharmacology agent.
• The research was conducted by L. Xie and colleagues at the University of California's Skaggs School of Pharmacy and Pharmaceutical Sciences.
• The study was published in Plos Computational Biology (Drug discovery using chemical systems biology: weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir. Plos Computational Biology, 2011;7(4):e1002037).

Statistics:

• Nelfinavir was found to inhibit 10-20% of the identified kinases in vitro.
• The computational predictions were validated by 80% concordance with in vitro kinase activity assays.
• The study identified 30 putative off-targets of Nelfinavir, which are involved in regulating cellular processes vital for carcinogenesis and metastasis.

Sources:

• Xie, L., et al. (2011). Drug discovery using chemical systems biology: weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir. Plos Computational Biology, 7(4), e1002037.
• Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego.