TY - JOUR
T1 - Screening for E3-Ubiquitin ligase inhibitors
T2 - Challenges and opportunities
AU - Landré, Vivien
AU - Rotblat, Barak
AU - Melino, Sonia
AU - Bernassola, Francesca
AU - Melino, Gerry
PY - 2014
Y1 - 2014
N2 - The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.
AB - The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.
KW - Clomipramine
KW - HECT
KW - High throughput screening
KW - ITCH
KW - P63
KW - P73
KW - Small molecular inhibitor
KW - Therapeutics
UR - http://www.scopus.com/inward/record.url?scp=84907831745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907831745&partnerID=8YFLogxK
M3 - Article
C2 - 25237759
AN - SCOPUS:84907831745
VL - 5
SP - 7988
EP - 8013
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 18
ER -