Theranostics 2021; 11(17):8337-8349. doi:10.7150/thno.62686


Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins

Jiayi Lin1*, Jinmei Jin1*, Yiwen Shen1*, Lijun Zhang1, Gang Gong1, Huiting Bian1, Hongzhuan Chen1, Dale G. Nagle3, Ye Wu1✉, Weidong Zhang1,2✉, Xin Luan1✉

1. Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
2. School of Pharmacy, Second Military Medical University, Shanghai, 201203, China
3. Department of Biomolecular Sciences and Research of Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Lin J, Jin J, Shen Y, Zhang L, Gong G, Bian H, Chen H, Nagle DG, Wu Y, Zhang W, Luan X. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics 2021; 11(17):8337-8349. doi:10.7150/thno.62686. Available from

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Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as “undruggable” before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.

Keywords: targeted protein degradation (TPD), extracellular and membrane proteins, LYTAC, AbTAC