Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

Vivien Landré, Barak Rotblat, Sonia Melino, Francesca Bernassola and Gerry Melino _

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Oncotarget. 2014; 5:7988-8013. https://doi.org/10.18632/oncotarget.2431

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Vivien Landré1, Barak Rotblat1, Sonia Melino2, Francesca Bernassola2 and Gerry Melino1,2

1 Medical Research Council, Toxicology Unit, Leicester, UK

2 Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy


Gerry Melino, email:

Keywords: HECT, ITCH, p73, p63, high throughput screening, therapeutics, clomipramine, small molecular inhibitor

Received: July 24, 2014 Accepted: September 02, 2014 Published: September 03, 2014


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.

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