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Summary of PROTAC And Other Targeted Protein Degradation Technologies
EP39489
Poster Title: Summary of PROTAC And Other Targeted Protein Degradation Technologies
Submitted on 04 Nov 2022
Author(s): Sonia Li
Affiliations: Biopharma PEG Scientific Inc.
Poster Views: 94
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Poster Information
Abstract: Proteolysis targeting chimeras (PROTACs) has come a long way since Crews first reported in 2001. At present, various degradation technologies based on PROTAC have been successfully developed for the degradation of kinases, nuclear receptors, epigenetic proteins, misfolded proteins and RNA. These technologies have greatly broadened the range of targets and clinical applications for diseases such as cancer, neurodegenerative diseases and viral diseases. To date, more than 15 PROTAC molecules have entered clinical trials. In this article, we summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.

Traditional small molecule inhibitors play a therapeutic role by interfering with protein function, while protein-targeted degraders play a role by proteasomal degradation of pathogenic target proteins, resulting in different biological effects, so they have higher selectivity and efficacy. Several targeted protein degradation strategies have been reported, among which the most famous is the proteolysis targeting chimera (PROTAC). In addition, researchers have also developed other types of degraders one after another, including intracellular click-formed proteolysis-targeting chimeras (CLIPTACs), photochemical targeting chimera (PHOTAC), semiconducting polymer nano-PROTAC (SPNpro), floate-PROTAC, antibody-PROTAC conjugate, antibody-based PROTAC (AbTAC), ribonuclease targeting chimera (RIBOTAC), transcription factor PROTAC (TF-PROTAC), chaperone-mediated protein degradation (CHAMP), biological PROTAC (bioPROTAC) and molecular glue, etc.

Summary of different targeted protein degraders

Figure 1. Summary of different targeted protein degraders

Targeted Protein Degradation Technologies
1. Proteolysis Targeting Chimeras (PROTACs)
Compared with other targeted protein degradation technologies, PROTAC has been more widely and deeply studied. It is composed of E3 ubiquitin ligase ligand, protein of interest (POI) ligand and linker. The formation of the POI-PROTAC-E3 ligase ternary complex can trigger the ubiquitination and degradation of POI through the ubiquitin-proteasome system. The concept of PROTAC was first proposed by Craig M. Crews in 2001. Many companies are involved in PROTAC, including Arvinas, Nurix Therapeutics, Kymera Therapeutics, C4 Therapeutics, Bristol-Myers Squibb and Novartis. Currently, at least 15 PROTACs have entered the clinic (Figure 2). Among them, the most advanced ones are the androgen receptor (AR) degrader ARV-110 for prostate cancer and the estrogen receptor (ER) degrader ARV-471 for breast cancer, which have entered phase II clinical trials in 2021.

PROTAC-targeted protein degraders

Figure 2. Summary of PROTACs entering clinical trials

PROTACs have successfully degraded various POIs, including kinases, nuclear receptors, epigenetic proteins, misfolded proteins, etc. According to statistics, about 3939 PROTACs have been reported so far, including 981 POI ligands, 74 E3 ligase ligands and 1100 linker chains. A variety of kinase degraders have been developed, such as the degradation of BCR-Abl, BTK, IRAK4 and EGFR. In addition, nuclear receptor degraders have been developed, such as the degradation of AR, ER and CRABPs (cellular retinoic acid binding proteins). There are also many cases of PROTACs targeting epigenetic proteins, such as: BET, STAT3, Trim24, BRD7/9 IKZF, HDAC6, Sirt2, PCAF/GCN5, etc. PROTAC technology has also been used to degrade pathogenic misfolded proteins, such as Tau protein and alpha-synuclein. Studies have shown that PROTACs can cross the blood-brain barrier for the treatment of neurodegenerative diseases.

In addition to cancer and neurodegenerative diseases, PROTACs can also treat immune diseases by targeting IRAK4, sirtuin and PCAF/GCN5, as well as viral infections by targeting HCV NS3/4A protease. For viral infectious diseases, viral RNA replication requires RNA-dependent RNA/DNA polymerases (RdRp/RdDp), none of which is present in the human body, and which possess highly conserved catalytic domains, making them important targets for a wide range of antiviral drugs. Therefore, PROTACs targeting RdRp/RdDp will have great clinical potential as pan-viral antivirals.
Summary: We summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.References: [1]. PROTACs: chimeric molecules that target proteins to the Skp1-Cullin-F boxcomplex for ubiquitination and degradation, Proc.Natl. Acad. Sci. U. S. A. 2001,98, 8554-8559.
[2].Targeted protein degraders crowd into the clinic, Nat. Rev. Drug Discov. 2021, 20, 247-250.
[3].PROTAC targeted protein degraders: the past is prologue, Nat. Rev. Drug Discov. 2022, 21, 181-200.
[4].Drugging the 'undruggable' cancer targets, Nat. Rev. Cancer 2017, 17, 502-508.
[5].New chemical modalities enabling specific RNA targeting and degradation: application to SARS-CoV-2 RNA, ACS Cent. Sci., 2020, 6, 1647-1650.
[6].Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4, ACS Chem. Biol. 2020, 15 ,1306-1312.
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