Cell cycle regulatory E3 ubiquitin ligases as anticancer targets.
Disregulation of the cell cycle and proliferation play key roles in cellular transformation and tumorigenesis. Such processes are intimately tied to the concentration, localization and activity of enzymes, adapters, receptors, and structural proteins in cells. Ubiquitination of these cellular regulatory proteins, governed by specific enzymes in the ubiquitin (Ub) conjugation cascade, has profound effects on their various functions, most commonly through proteasome targeting and degradation. This review will focus on a variety of E3 Ub ligases as potential oncology drug targets, with particular emphasis on the role of these molecules in the regulation of stability, localization, and activity of key proteins such as tumor suppressors and oncoproteins. E3 ubiquitin ligases that have established roles in cell cycle and apoptosis, such as the anaphase-promoting complex (APC), the Skp-1-Cul1-F-box class, and the murine double minute 2 (MDM2) protein, in addition to more recently discovered E3 ubiquitin ligases which may be similarly important in tumorigenesis, (e.g. Smurf family, CHFR, and Efp), will be discussed. We will present evidence to support E3 ligases as good biological targets in the development of anticancer therapeutics and address challenges in drug discovery for these targets.
Pray
Todd R
TR
Rigel Pharmaceuticals, Inc., 240 East Grand Avenue, South San Francisco, California 94080, USA. tpray@rigel.com
Parlati
Francesco
F
Huang
Jianing
J
Wong
Brian R
BR
Payan
Donald G
DG
Bennett
Mark K
MK
Issakani
Sarkiz Daniel
SD
Molineaux
Susan
S
Demo
Susan D
SD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D025801:Ubiquitin / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D008025:Ligases