A new target for cancer therapy.

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Teresa A. Soucy et al.
Nature 458, 732-736 (9 April 2009)

This group of authors has discovered a compound that inhibits the never-before-targeted NEDD8-activating enzyme (NAE), and show that this compound suppresses the growth of human lung-tumour tissue transplanted into mice.

The new drug principally targets the ubiquitin-proteasome system (UPS). One of main disadvantages in targeting the UPS is its non-specificity. A wide variety of vital cellular processes are intimately liked to the UPS. However, the UPS was shown to be a effective target for cancer chemotherapeutics when Bortezomib, a E3 ligase inhibitor, was successfully developed for the treatment of refractory multiple myeloma.

This paper reports a clever way around the problem of non-specificity of the UPS. Instead of targeting E3 ligase enzymes directly, they targeted NEDD8-activating enzyme (NAE), which is required to activate a subset of E3 enzymes known as cullin-RING ubiquitin ligases (CRLs). Inhibition of NAE leads to the accumulation of the substrates of CRLs in the cell. This induced apoptosis in the proliferating cancer cells possibly as a result of the deregulation of DNA synthesis. This phenomenon was already seen in vitro when cancer cell lines were exposed to this drug. What is most interesting and promising is the fact that the authors report nearly complete regression of transplanted human lung-tumour tissue in the drug-treated mice, with no obvious side effects. It remains unclear, however, why a drug that inactivates so many different CRLs (presumably also those in healthy cells) should kill only cancer cells.

These are exciting findings, but it is prudent to remember that many promising drug candidates have been shown to cure cancer in mice, only to fail spectacularly in humans. It remains to be seen whether it will become the second marketed drug that deliberately targets components of the UPS after Bortezomib.