E3 ubiquitin ligases are a large family of proteins that can be classified into 
three major structurally distinct types: N-end rule E3s, E3s containing the HECT 
(Homology to E6AP C-Terminus) domain, and E3s with the RING (Really Interesting 
New Gene) finger, including its derivatives, the U- Box and the PHD (Plant 
Homeo-Domain). E3 ubiquitin ligases exist as single polypeptide or multimeric 
complexes. Together with ubiquitin activating enzyme E1 and ubiquitin 
conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a 
variety of protein substrates for targeted degradation via the 26S proteasome. 
E3 ubiqutin ligases, therefore, play an essential role in regulation of many 
biological processes. Furthermore, E3s are enzymes that determine the 
specificity of protein substrates; they represent a class of "drugable" targets 
for pharmaceutical intervention. In this review, I will mainly focus on E3 
ubiquitin ligases as potential cancer targets and discuss three of the most 
promising E3s, Mdm2/Hdm2, IAPs, and SCF, for their target rationales, target 
validation, and critical issues associated with them. These E3 ligases or their 
components are overexpressed in many human cancers and their inhibition leads to 
growth suppression or apoptosis. In addition, I will evaluate two current 
methodologies available for the high throughput screening for small molecular 
weight chemical inhibitors of the E3 ubiquitin ligases. Although targeting E3 
ubiquitin ligases is still in its infancy, speedy approval of the general 
proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of 
relapsed and refractory multiple myeloma suggests the promise of specific E3 
inhibitors in anti-cancer therapy. Emerging technologies, such as siRNA, will 
provide a better validation of many E3s. It is anticipated that E3 ubiquitin 
ligases will represent an important new target platform for future 
mechanism-driven drug discovery.