Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology

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The Proteolysis-Targeting Chimeras, also known as Protacs, looks like dumbbells, connecting "ligands of interest proteins" and "recruitment ligands of E3 ubiquitin ligases" through a "linker". In other words, one end of the Protac® molecule binds to the target protein, and the other end binds to E3 ubiquitin ligase. E3 ubiquitin ligase can mark a small protein called ubiquitin as defective or damaged by attaching it to the target protein. After that, the cell's protein shredder (proteasome) degrades the labeled target protein.

Schematic diagram of the mode of action of Protacs (source: Royal Society of Chemistry)Schematic diagram of the mode of action of Protacs (source: Royal Society of Chemistry)

In March 2019, Nature reported that protein degradants based on Protacs technology will become the next blockbuster drug. In the past two years, research in academia frequently yielded results related to Protacs. In the pharmaceutical industry, drug research and development based on this technology has become a new focus. Enthusiasm for Protacs are ranging from start-ups to pharmaceutical giants. What is worth mentioning is that with the disclosure of positive phase I clinical data of ARV-110, the world's first small molecular protein degrader based on Protacs, confidence in the clinical transformation of this technology has greatly increased.

Recently, a monograph entitled "Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology" and edited by Professor Craig Crews of Yale University, a pioneer of Protacs technology, and Hilmar Weinmann, a scientist at Janssen Pharmaceuticals, has been officially released. The book, with 15 chapters and 359 pages, provides a comprehensive overview of the recent research progress from leading scientists in the field and some of the present challenges.

Targeted degradation of proteins by small molecules is one of the most exciting small molecule therapy strategies in decades, and it is also a rapidly developing research field. In particular, the development of Protacs has opened up a new way to target proteins that are traditionally difficult to target. This book would be ideal for researchers in the fields of drug development and chemical biology.

In the first chapter, Professors Craig Crews, Hilmar Weinmann, and Bayer scientist Philipp M. Cromm reviewed the development of Protacs and discussed the optimization of Protacs and whether the targeted degradation mediated by this technology can change the paradigm of drug development.

The article pointed out that from the publication of the first proof-of-concept study in 2001 to the first clinical trial of Protacs in 2019, this technique has developed into a chemical biological method and a new treatment.

In the early stage of the development of this technology, the E3 ligase binding motif of Protacs was peptide, which led to limited cell permeability and poor degradation of Protacs. With the development of more drug-like VHL E3 ligase pseudo-peptide ligands and the elucidation of the mode of action of thalidomide, Protacs technology has made a breakthrough. These findings also paved the way for the development of the first drug-like Protacs targeting RIPK2/ERRα12 and BRD4 reported in 2015. As these pioneering studies have greatly accelerated the development of this field, academic and industrial interest in Protacs-induced protein degradation has greatly increased. Since then, many research groups have focused on exploring the strengths, opportunities, limitations and weaknesses of the technology.

At present, the Arvinas pioneered two clinical trials in 2019, one aimed at investigating ARV-110, a small molecule protein degrader targeting androgen receptor (AR) for patients with metastatic ER+-positive/HER2-negative breast cancer, and the other is to study ARV-471, a small molecule protein degrader targeting estrogen receptor (ER) for patients with metastatic castration-resistant prostate cancer.

In terms of target selection, in addition to the previously mentioned targets such as AR, ER and BRD4, a large number of proteins have become the choice of researchers in the field of Protacs since 2001. The following table summarizes most of the reported Protacs targets and corresponding E3 ligases in chronological order.

Table 1 Some proteins that have been successfully degraded by Protacs ubiquitin pathway

YearTargetTarget classE3 ligase
2001MetAP2DimetallohydrolaseβTRCP (polypeptidic)
2003Androgen receptorNuclear receptorβTRCP (polypeptidic)
 Estrogen receptorNuclear receptorβTRCP (polypeptidic)
2004Androgen receptorNuclear receptorVHL (polypeptidic)
2007Aryl hydrocarbon receptorTranscription factorVHL (polypeptidic)
2008Androgen receptorNuclear receptorMDM2 (nutlin-3a)
 Estrogen receptorNuclear receptorVHL (polypeptidic)
2010CRAPBPI and CRAPBPIICellular retinoic acid-binding proteinscIAP (small molecule)
2011RARNuclear receptorcIAP (small molecule)
 Androgen receptorNuclear receptorcIAP (small molecule)
 Estrogen receptorNuclear receptorcIAP (small molecule)
2013FRS2aFibroblast growth factor receptor substrate 2VHL(polypeptidic)
 PI3KKinaseVHL (polypeptidic)
2014TACC3Transforming acidic coiled-coil-containing protein 3cIAP (small molecule)
2015BRD4BromodomainVHL (small molecule)
 BET (BRD2, BRD3,BRD4)BromodomaincIAP (small molecule)
 ERRONuclear receptorVHL (small molecule)
 FKBP12Peptidyl-prolyl cis-trans isomeraseCRBN (small molecule)
 RIPK2KinaseVHL (small molecule)
2016AKTKinaseCRBN (small molecule)
 BCR-ABLKinaseVHL (small molecule),CRBN (small molecule)
 BET (BRD2, BRD3,BRD4)BromodomainVHL (small molecule)
 TauMicrotubule-a ssociated protein tauVHL (polypeptidic)
2017CDK9KinaseCRBN (small molecule)
 VHLE3 ligaseVHL (small molecule)
2018TBK1KinaseVHL (small molecule)
 BTKKinaseCRBN (small molecule)
 TRIM24BromodomainVHL (small molecule)
 PCAF/GCN5BromodomainCRBN (small molecule)
 ALKKinaseCRBN (small molecule)
2019PI3KKinaseCRBN (small molecule)
 HDAC6Histone deacetylaseCRBN (small molecule)
 BET (BRD2, BRD3,BRD4, BRDT)BromodomainCRBN (small molecule)
 Sirt2Lysine deacetylaseCRBN (small molecule)
 BCL6Transcriptional regulatorCRBN (small molecule)
 CRBNE3 Ligase CRBN (small molecule)
 PTK2/FAKKinaseVHL (small molecule)
 FLT-3KinaseVHL (small molecule)
 EGFR, HER2, and c-MetKinaseVHL (small molecule)
 IRAK4KinaseVHL (small molecule)
 Mcl-1/Bcl-2Bcl-2 familyCRBN (small molecule)
 PTK2/FAKKinaseVHL (small molecule)
 PARP1Poly (ADP-ribose) polymerasesMDM2 (nutlin-3)
 CDK6KinaseCRBN (small molecule)
 BRD9/BRD7BromodomainVHL (small molecule)
 CRBNE3 ligaseVHL (small molecule)
 EGFRKinaseCRBN (small molecule)
 Estrogen receptorNuclear receptorVHL (small molecule)
 Androgen receptorNuclear receptorVHL (small molecule)
 MDM2E3 ligaseCRBN (small molecule)
 HDAC6Histone deacetylaseCRBN (small molecule)
 SMARCA2,SMARCA4,PBRM1BromodomainVHL (small molecule)
 BRD4BromodomainRNF114 (nimbolide)
 SGK3KinaseVHL (small molecule)
 BRD4BromodomainRNF4 (covalent binding small molecule)
 HCV NS3/4AProteaseCRBN (small molecule)


  1. Weinmann, H., & Crews, C. (Eds.). (2020). Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology. Royal Society of Chemistry.
  2. Paiva, S. L., & Crews, C. M. (2019). Targeted protein degradation: elements of Protac® design. Current opinion in chemical biology50, 111-119.
  3. Guo, J., Liu, J., & Wei, W. (2019). Degrading proteins in animals:“Protac®” tion goes in vivo. Cell research29(3), 179-180.

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