{"id":2229,"date":"2020-11-03T15:51:00","date_gmt":"2020-11-03T15:51:00","guid":{"rendered":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/?p=2229"},"modified":"2026-01-26T16:28:03","modified_gmt":"2026-01-26T16:28:03","slug":"e3-ligase-ligands-for-protacs","status":"publish","type":"post","link":"https:\/\/sites.dundee.ac.uk\/alessio-ciulli\/2020\/11\/03\/e3-ligase-ligands-for-protacs\/","title":{"rendered":"E3 ligase ligands for PROTACs"},"content":{"rendered":"

Our review covering E3 ligase ligands for PROTACs is now published in SLAS Discovery<\/p>\n

Congratulations to Tasuku on this article. We hope people will find this review useful!<\/p>\n

Read the Open Access full article<\/a>.<\/p>\n

Authors<\/strong>: Tasuku Ishida and Alessio Ciulli*<\/p>\n

Title<\/strong>: E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones<\/p>\n

Abstract<\/strong><\/h2>\n

Bifunctional degrader molecules, also called proteolysis-targeting chimeras\u2009(PROTACs),\u2009are\u2009a new modality of chemical tools and potential therapeutics\u2009to understand and treat human disease.\u2009A\u2009required PROTAC\u2009component is\u2009a\u2009ligand binding to an E3 ubiquitin ligase, which is then joined to another ligand binding to a protein to be degraded\u2009via the ubiquitin\u2013proteasome system. The advent of nonpeptidic\u2009small-molecule E3 ligase ligands, notably for von Hippel\u2013Lindau (VHL) and\u2009cereblon\u2009(CRBN), revolutionized the field and\u2009ushered\u2009in the design of drug-like PROTACs with potent and selective degradation activity. A first wave of PROTAC drugs are now undergoing clinical development in cancer, and the field is seeking to extend the repertoire of chemistries that allow hijacking new E3 ligases to improve the scope of targeted protein degradation.\u00a0 Here, we\u2009briefly\u2009review\u2009how\u2009traditional E3 ligase ligands\u2009were discovered, and then outline approaches and ligands\u2009that have been recently used\u2009to discover new\u2009E3 ligases\u2009for PROTACs.\u2009We will then\u2009take an outlook at\u2009current and\u2009future\u2009strategies undertaken that invoke either target-based screening or phenotypic-based approaches, including the use of\u2009DNA-encoded libraries (DELs), display technologies and cyclic peptides, smaller molecular glue degraders, and covalent warhead ligands. These approaches are ripe for expanding the chemical space of PROTACs and usher in the advent of other emerging bifunctional modalities of proximity-based pharmacology.
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