New Anti-Cancer Drug Takes Out Proteasome Supply Line

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New Anti-Cancer Drug Takes Out Proteasome Supply Line 5/4/2009

The ubiquitin-proteasome system (UPS) is responsible for degrading intracellular proteins and has roles in many cellular functions, including some that drive cancer growth. Covalent linkage of the small polypeptide ubiquitin to a protein frequently targets the protein for degradation by the proteasome. For reasons that remain poorly understood, some cancers are exquisitely sensitive to even small decreases in UPS activity. The proteasome inhibitor bortezomib has emerged as an exciting antitumor drug and is FDA approved for the treatment of myeloma and mantle cell lymphoma. Hence, there is great interest in targeting other components of the UPS as a strategy to attack cancer. Tagging a protein with ubiquitin involves 3 distinct enzymatic steps. Ubiquitin must be “activated” in an ATP-dependent reaction by a ubiquitin-activating enzyme (E1). The activated ubiquitin is transferred from the E1 to a ubiquitin-conjugating enzyme (E2). A ubiquitin-ligase enzyme (E3) links ubiquitin to the substrate protein targeted for degradation. In humans, there are ~650 ubiquitin E3 ligases, a portion of which are positively regulated by an enzyme called NAE (NEDD8 activating enzyme). Given its linchpin role in the ubiquitinylation of proteins, NAE represents a prime target for drugging the UPS. NAE inihibitor shows promise Researchers at Millennium Pharmaceuticals (Cambridge, Mass.) recently reported MLN4924, a potent and highly selective inhibitor of NAE with strong anti-cancer activity in preclinical studies. At nM concentrations, MLN4924 strongly induced apoptosis of cultured lung and colorectal carcinoma cell lines through deregulation of DNA synthesis. Moreover, the drug led to near complete growth inhibition of these human tumor cells when transplanted into mice with no obvious side effects. On the basis of these promising results, Millennium is initiating phase 1 clinical trials of MNL4924 in humans and hopes that it becomes the second marketed drug to target a component of the UPS. For more information: Soucy TA, Smith PG, Milhollen MA, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458:732-736.