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PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras

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Abstract

In the recent past, proteolysis-targeting chimera (PROTAC) technology has received enormous attention for its ability to overcome the limitations of protein inhibitors and its capability to target undruggable proteins. The PROTAC molecule consists of three components, a ubiquitin E3 ligase ligand, a linker, and a target protein ligand. The application of this technology is rapidly gaining momentum, especially in cancer therapy. In this review, we first look at the history of degraders, followed by a section on the ubiquitin proteasome system (UPS) and E3 ligases used in PROTAC development. PROTACs are dependent on the UPS for degradation of target proteins. We further discuss the scope and design of degraders and mitigation strategies for overcoming the hook effect seen with degraders. As PROTACs do not follow Lipinski’s ‘Rule of 5’, these molecules face drug metabolism and pharmacokinetic challenges. A detailed section on absorption, distribution, metabolism, and excretion of degraders is provided wherein we discuss methodologies and strategies to surmount the challenges faced by these molecules. For understanding PROTAC-mediated degradation, the characterization and measurement of protein levels in cells is important. Currently used techniques and recent advancements in assessment tools for degraders are discussed. Furthermore, we examine the challenges and emerging technologies that need to be focused on in order to competently develop potent degraders. Many companies are working in this area of emerging new modality and a few PROTACs have already entered clinical trials; the details of the trials are included in this review.

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  1. Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Electronic City, Phase-2, Bangalore, 560100, India

    Jyotsana Madan, Vijay Kamal Ahuja, Susanta Samajdar, Murali Ramchandra & Sanjeev Giri

  2. Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia

    Kamal Dua

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JM, VKA, and KD made substantial contributions to the conception, writing and design of this manuscript. SS, SG, and MR revised the manuscript critically for important intellectual content and approved the version to be published. JM, VKA, KD, SS, MR, and SG agree to be accountable for all aspects of this work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Jyotsana Madan, Vijay Kamal Ahuja, Susanta Samajdar, Murali Ramchandra, and Sanjeev Giri are employees of Aurigene Discovery Technologies Limited, Bangalore, and have no conflicts of interest that might be relevant to the contents of this manuscript. Kamal Dua declares that he has no conflicts of interest that might be relevant to the contents of this manuscript.

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Madan, J., Ahuja, V.K., Dua, K. et al. PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras. BioDrugs 36, 609–623 (2022). https://doi.org/10.1007/s40259-022-00551-9

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