Proteolysis targeting chimera

Short description: Small molecule (PROTAC)

TL 12-186, a thalidomide-based PROTAC targeting the protein GSPT1, a translation termination factor[1]

A proteolysis targeting chimera (PROTAC)[2] is a molecule that can remove specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. A heterobifunctional molecule with two active domains and a linker, PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein. Recruitment of the E3 ligase to the target results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity (rather than inhibit the target protein's enzymatic activity), efforts are underway to retool previously ineffective inhibitor molecules as PROTACs.[3][4]

## Contents

* 1 History
* 2 Mechanism of action
* 3 Design and development
* 4 Benefits
* 5 PROTAC databases
* 6 References

## History

Kathleen Sakamoto, Craig Crews and Ray Deshaies initially described PROTACs in 2001.[5] PROTAC technology has been applied by drug discovery labs using various E3 ligases,[6] including pVHL,[7][8][9] CRBN,[10][11] Mdm2,[12] beta-TrCP1,[5] DCAF11,[13][14] DCAF15,[15] DCAF16,[15] RNF114,[15] and c-IAP1.[16] Yale University licensed the PROTAC technology to Arvinas in 2013–14.[17][18]

In 2019, Arvinas put two PROTACs into clinical trials: bavdegalutamide (ARV-110), an androgen receptor degrader, and vepdegestrant (ARV-471), an estrogen receptor degrader.[19][20] In 2021, Arvinas put a second androgen receptor PROTAC, Luxdegalutamide (ARV-766), into the clinic.[21]

In 2025, Johnson & Johnson acquired PROTACs maker Halda Therapeutics for $3 billion.[2]

## Mechanism of action

Mechanism. E1, E2, E3: ubiquitination enzymes; Ub = ubiquitin; target = protein to be degraded[1]

PROTACs achieve degradation through "hijacking" the cell's ubiquitin–proteasome system (UPS) by bringing together the target protein and an E3 ligase.[22]

First, the E1 activates and conjugates the ubiquitin to the E2.[15] The E2 then forms a complex with the E3 ligase. The E3 ligase targets proteins and covalently attaches the ubiquitin to the protein of interest.[22] Eventually, after a ubiquitin chain is formed, the protein is recognized and degraded by the 26S proteasome.[19] PROTACs take advantage of this cellular system by putting the protein of interest in close proximity to the E3 ligase to catalyze degradation.[19]

Unlike traditional inhibitors, PROTACs have a catalytic mechanism, with the PROTAC itself being recycled after the target protein is degraded.[19]

## Design and development

The protein targeting warhead, E3 ligase, and linker must all be considered for PROTAC development. Formation of a ternary complex between the protein of interest, PROTAC, and E3 ligase may be evaluated to characterize PROTAC activity because it often leads to ubiquitination and subsequent degradation of the targeted protein.[15] A hook effect is commonly observed with high concentrations of PROTACs due to the bifunctional nature of the degrader.[15]

Currently, pVHL and CRBN have been used in preclinical trials as E3 ligases.[15] However, there still remains hundreds of E3 ligases to be explored, with some giving the opportunity for cell specificity.

Additionally, there have been attempts to produce PROTACs which target bacteria (BacPROTAC) as a way of circumventing antibiotic resistance. These BacPROTACs target the ClpC:ClpP protease system, an analogue with similar function to E3 ubiquitin ligase in bacterial cells.[23]

## Benefits

Compared to traditional inhibitors, PROTACs display multiple benefits that make them desirable drug candidates. Due to their catalytic mechanism, PROTACs can be administered at lower doses compared to their inhibitor analogues,[20] though care needs to be taken in achieving oral bioavailability if administered by that route.[24] Some PROTACs have been shown to be more selective than their inhibitor analogues, reducing off-target effects.[20] PROTACs have the ability to target previously undruggable proteins, as they do not need to target catalytic pockets.[20] This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors.

## PROTAC databases

* BioGRID is an open public resource containing manually curated molecular interaction data.[25] In addition to its extensive catalogue of genetic and protein interactions, BioGRID also curates chemical interactions including experimentally-determined PROTACs and PROTAC-related molecules with accompanying target and E3 information.
* PROTACpedia, a manually curated and user-contributed PROTAC-specific public access database.
* E3 Atlas, a comprehensive E3 database that characterizes the potential for specific E3 ligases to be employed for PROTAC design.[26]

## References

1. ↑ 1.0 1.1 "Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders". ACS Chemical Biology 13 (3): 553–560. March 2018. doi:10.1021/acschembio.7b00969. PMID 29356495.
2. ↑ 2.0 2.1 "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie 59 (36): 15448–15466. September 2020. doi:10.1002/anie.202004310. PMID 32428344.
3. ↑ "Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation". Molecules 23 (8): 1958. August 2018. doi:10.3390/molecules23081958. PMID 30082609.
4. ↑ "TACkling Cancer by Targeting Selective Protein Degradation". Pharmaceutics 15 (10): 2442. October 2023. doi:10.3390/pharmaceutics15102442. PMID 37896202.
5. ↑ 5.0 5.1 "Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation". Proceedings of the National Academy of Sciences of the United States of America 98 (15): 8554–8559. July 2001. doi:10.1073/pnas.141230798. PMID 11438690. Bibcode: 2001PNAS...98.8554S.
6. ↑ "Drug developers delve into the cell's trash-disposal machinery". Nature Reviews. Drug Discovery 15 (5): 295–297. May 2016. doi:10.1038/nrd.2016.86. PMID 27139985.
7. ↑ "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4". ACS Chemical Biology 10 (8): 1770–1777. August 2015. doi:10.1021/acschembio.5b00216. PMID 26035625.
8. ↑ "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature Chemical Biology 11 (8): 611–617. August 2015. doi:10.1038/nchembio.1858. PMID 26075522.
9. ↑ "HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins". ACS Chemical Biology 10 (8): 1831–1837. August 2015. doi:10.1021/acschembio.5b00442. PMID 26070106.
10. ↑ "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry & Biology 22 (6): 755–763. June 2015. doi:10.1016/j.chembiol.2015.05.009. PMID 26051217.
11. ↑ "DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation". Science 348 (6241): 1376–1381. June 2015. doi:10.1126/science.aab1433. PMID 25999370.
12. ↑ "Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics". Bioorganic & Medicinal Chemistry Letters 18 (22): 5904–5908. November 2008. doi:10.1016/j.bmcl.2008.07.114. PMID 18752944.
13. ↑ "DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras". Journal of the American Chemical Society 143 (13): 5141–5149. April 2021. doi:10.1021/jacs.1c00990. PMID 33783207.
14. ↑ "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype". Nature Communications 14 (1): 7908. November 2023. doi:10.1038/s41467-023-43657-6. PMID 38036533. Bibcode: 2023NatCo..14.7908X.
15. ↑ 15.0 15.1 15.2 15.3 15.4 15.5 15.6 "Proteolysis targeting chimeras (PROTACs) in cancer therapy". Journal of Experimental & Clinical Cancer Research 39 (1): 189. September 2020. doi:10.1186/s13046-020-01672-1. PMID 32933565.
16. ↑ "Design, synthesis and biological evaluation of nuclear receptor-degradation inducers". Bioorganic & Medicinal Chemistry 19 (22): 6768–6778. November 2011. doi:10.1016/j.bmc.2011.09.041. PMID 22014751.
17. ↑ "Connecticut to support New Haven biotech to the tune of $4.25 million". New Haven Register. 2013-09-26. http://www.nhregister.com/general-news/20130926/connecticut-to-support-new-haven-biotech-to-the-tune-of-425-million.
18. ↑ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. https://www.bostonglobe.com/business/2016/05/19/scientist-wants-hijack-cells-tiny-garbage-trucks-fight-cancer/zTINEWqETJ3gZEJfBjfFOO/story.html?s_campaign=email_BG_TodaysHeadline&s_campaign.
19. ↑ 19.0 19.1 19.2 19.3 "The PROTACtable genome". Nature Reviews. Drug Discovery 20 (10): 789–797. October 2021. doi:10.1038/s41573-021-00245-x. PMID 34285415.
20. ↑ 20.0 20.1 20.2 20.3 "From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation". Frontiers in Chemistry 9. 2021. doi:10.3389/fchem.2021.672267. PMID 33959589. Bibcode: 2021FrCh....9..215C.
21. ↑ "A Study of ARV-766 Given by Mouth in Men With Metastatic Prostate Cancer". ClinicalTrialsGov. https://clinicaltrials.gov/study/NCT05067140?intr=ARV-766&rank=1.
22. ↑ 22.0 22.1 "Targeted Protein Degradation by Small Molecules". Annual Review of Pharmacology and Toxicology 57: 107–123. January 2017. doi:10.1146/annurev-pharmtox-010715-103507. PMID 27732798.
23. ↑ "BacPROTACs mediate targeted protein degradation in bacteria". Cell 185 (13): 2338–2353. June 2022. doi:10.1016/j.cell.2022.05.009.
24. ↑ "Structural and Physicochemical Features of Oral PROTACs". Journal of Medicinal Chemistry 67 (15): 13106–13116. August 2024. doi:10.1021/acs.jmedchem.4c01017. PMID 39078401.
25. ↑ "The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions". Protein Science 30 (1): 187–200. January 2021. doi:10.1002/pro.3978. PMID 33070389.
26. ↑ "Expanding PROTACtable genome universe of E3 ligases". Nature Communications 14 (1): 6509. October 2023. doi:10.1038/s41467-023-42233-2. PMID 37845222. Bibcode: 2023NatCo..14.6509L.

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