Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer.
E3 ubiquitin ligases regulate many dynamic cellular processes important for cancer cell survival. Together with ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzymes (E2s), E3s catalyze the ubiquitination of numerous protein substrates that are subsequently targeted to the 26S proteasome for degradation. The clinical success of the proteasome inhibitor bortezomib has encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention. Targeting specific E3s is particularly attractive because there is the potential to selectively block the degradation of certain cellular proteins and possibly avoid unwanted effects on other proteins. The cullin-RING ubiquitin E3 ligases (CRLs) represent the largest subfamily of E3s. The requirement that CRLs be activated by NEDD8 modification on the cullin protein offers an "achilles heel" for modulating this entire subfamily. NEDD8-activating enzyme (NAE) catalyzes the first step in the NEDD8 pathway and as such controls the activity of CRLs. In this article, we describe the role of the NEDD8 pathway in activating CRLs and discuss the preclinical findings with a first-in-class NAE inhibitor that is currently in phase I clinical trials for both solid tumor and hematological malignancies. In addition, we speculate where NAE inhibitors may find clinical utility.
Soucy
Teresa A
TA
Discovery, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. teresa.soucy@mpi.com
Smith
Peter G
PG
Rolfe
Mark
M
D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001897:Boronic Acids / Q000378:metabolism / Q000627:therapeutic use*; D000069286:Bortezomib; D044842:Cullin Proteins / Q000378:metabolism; D003517:Cyclopentanes / Q000378:metabolism; D006801:Humans; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000378:metabolism / Q000627:therapeutic use*; D011743:Pyrimidines / Q000378:metabolism; D054829:RING Finger Domains / Q000502:physiology; D015398:Signal Transduction; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D044842:Cullin Proteins; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D014452:Ubiquitins; D000069286:Bortezomib; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes; C539933:pevonedistat