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Updated: Jun 25, 2026

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
Published on: August 27, 2021
Approaches to discovering drugs that regulate E3 ubiquitin ligases
1Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. jhuang@rigel.com
Abstract:
The ubiquitin-proteasome system (UPS) plays an essential role in a wide variety of cell regulatory signaling pathways. The clinical effectiveness of the proteasome inhibitor Velcade in the treatment of several human cancers underscores the importance of the UPS as a novel target area for pharmaceutical intervention. E3 ubiquitin ligases are key enzyme complexes that regulate and determine the ubiquitination of specific substrates, whose abnormal regulation has been implicated in multiple disease phenotypes. Targeting a selective E3 ligase may allow specific manipulation of distinct pathways and eventually lead to a better therapeutic index with reduced nonspecific side effects. Here, we aim to discuss the challenges of interfering with small molecules in this target class, as well as current strategies and progress in E3 ligase drug discovery.
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