Review

Recent advancements in the discovery of cereblon-based protease-targeted chimeras with potential for therapeutic intervention

https://orcid.org/0000-0002-1949-2143

Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA

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Devendra K Agrawal

*Author for correspondence: Tel.: +1 909 469 7040;

E-mail Address: DAgrawal@WesternU.edu

https://orcid.org/0000-0001-5445-0013

Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA

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Published Online:1 Sep 2022https://doi.org/10.4155/fmc-2022-0149

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Abstract

Protease-targeted chimeras (PROTACs) have been employed as a novel therapeutic approach, utilizing the ubiquitin-proteasome system for targeted protein degradation. PROTACs are heterobifunctional molecules consisting of an E3 ligase ligand and a small-molecule inhibitor for recruiting a protein of interest. After binding, PROTAC molecules recruit E3 ligase for ubiquitination of the protein of interest, which is followed by its proteasome-mediated degradation. PROTAC molecules have several advantages over traditional small-molecule inhibitors. A number of PROTAC molecules based on small-molecule inhibitors have been developed against various diseases, among which cereblon-based PROTAC molecules have received the greatest interest due to their promising clinical use. This article highlights the current trends in the discovery of cereblon-based PROTAC molecules along with their medicinal chemistry, clinical progression and future outlook in cancers, cardiovascular diseases and neurodegenerative disorders.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 14, No. 19

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Received 27 June 2022

Accepted 5 August 2022

Published online 1 September 2022

Published in print October 2022

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Financial & competing interest disclosure

The research of DK Agrawal is supported by research grants R01 HL144125 and R01 HL147662 from the National Institutes of Health, USA. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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