Proteolysis targeting chimera explained

A proteolysis targeting chimera (PROTAC)[1] 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 meant for degradation. Recruitment of the E3 ligase to the target protein 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), there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.[2] [3]

Initially described by Kathleen Sakamoto, Craig Crews and Ray Deshaies in 2001,[4] the PROTAC technology has been applied by a number of drug discovery labs using various E3 ligases,[5] including pVHL,[6] [7] [8] CRBN,[9] [10] Mdm2,[11] beta-TrCP1, DCAF15,[12] DCAF16, RNF114, and c-IAP1.[13] Yale University licensed the PROTAC technology to Arvinas in 2013–14.[14] [15]

In 2019, Arvinas put two PROTACs into clinical trials: bavdegalutamide (ARV-110), an androgen receptor degrader, and vepdegestrant (ARV-471), an estrogen receptor degrader.[16]

Mechanism of action

PROTACs achieve degradation through "hijacking" the cell's ubiquitin–proteasome system (UPS) by bringing together the target protein and an E3 ligase.[17]

First, the E1 activates and conjugates the ubiquitin to the E2. 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. Eventually, after a ubiquitin chain is formed, the protein is recognized and degraded by the 26S proteasome. PROTACs take advantage of this cellular system by putting the protein of interest in close proximity to the E3 ligase to catalyze degradation.

Unlike traditional inhibitors, PROTACs have a catalytic mechanism, with the PROTAC itself being recycled after the target protein is degraded.[18]

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. A hook effect is commonly observed with high concentrations of PROTACs due to the bifunctional nature of the degrader.

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

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, though care needs to be taken in achieving oral bioavailability if administered by that route.[19] Some PROTACs have been shown to be more selective than their inhibitor analogues, reducing off-target effects. PROTACs have the ability to target previously undruggable proteins, as they do not need to target catalytic pockets. This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors.

PROTAC databases

Notes and References

  1. Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective . Angewandte Chemie International Edition. 2020 . 10.1002/anie.202004310 . Luh . Laura M. . Scheib . Ulrike . Juenemann . Katrin . Wortmann . Lars . Brands . Michael . Cromm . Philipp M. . 59 . 36 . 15448–15466 . 32428344 . 7496094 .
  2. Cermakova K, Hodges HC . Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation . Molecules . 23 . 8 . 1958 . August 2018 . 30082609 . 6102721 . 10.3390/molecules23081958 . free .
  3. Noblejas-López . María del Mar . Tébar-García . David . López-Rosa . Raquel . Alcaraz-Sanabria . Ana . Cristóbal-Cueto . Pablo . Pinedo-Serrano . Alejandro . Rivas-García . Lorenzo . Galán-Moya . Eva M. . October 2023 . TACkling Cancer by Targeting Selective Protein Degradation . Pharmaceutics . en . 15 . 10 . 2442 . 10.3390/pharmaceutics15102442 . 37896202 . 10610449 . 1999-4923 . free .
  4. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ . 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 . 8554–9 . July 2001 . 11438690 . 37474 . 10.1073/pnas.141230798 . 2001PNAS...98.8554S . free .
  5. Chi KR . Drug developers delve into the cell's trash-disposal machinery . Nature Reviews. Drug Discovery . 15 . 5 . 295–7 . May 2016 . 27139985 . 10.1038/nrd.2016.86 . 34652880 .
  6. Zengerle M, Chan KH, Ciulli A . Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4 . ACS Chemical Biology . 10 . 8 . 1770–7 . August 2015 . 26035625 . 4548256 . 10.1021/acschembio.5b00216 .
  7. Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, Mulholland KE, Routly N, Buckley DL, Gustafson JL, Zinn N, Grandi P, Shimamura S, Bergamini G, Faelth-Savitski M, Bantscheff M, Cox C, Gordon DA, Willard RR, Flanagan JJ, Casillas LN, Votta BJ, den Besten W, Famm K, Kruidenier L, Carter PS, Harling JD, Churcher I, Crews CM . 6 . Catalytic in vivo protein knockdown by small-molecule PROTACs . Nature Chemical Biology . 11 . 8 . 611–7 . August 2015 . 26075522 . 4629852 . 10.1038/nchembio.1858 .
  8. Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM . HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins . ACS Chemical Biology . 10 . 8 . 1831–7 . August 2015 . 26070106 . 4629848 . 10.1021/acschembio.5b00442 .
  9. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. June 2015. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry & Biology. 22. 6. 755–63. 10.1016/j.chembiol.2015.05.009. 4475452. 26051217.
  10. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. June 2015. Drug Development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 348. 6241. 1376–81. 10.1126/science.aab1433. 4937790. 25999370.
  11. Schneekloth AR, Pucheault M, Tae HS, Crews CM . Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics . Bioorganic & Medicinal Chemistry Letters . 18 . 22 . 5904–8 . November 2008 . 18752944 . 3175619 . 10.1016/j.bmcl.2008.07.114 .
  12. Ocaña. Alberto. Pandiella. Atanasio. 2020-09-15. Proteolysis targeting chimeras (PROTACs) in cancer therapy. Journal of Experimental & Clinical Cancer Research . 39. 1. 189. 10.1186/s13046-020-01672-1. 1756-9966. 7493969. 32933565 . free .
  13. Itoh Y, Kitaguchi R, Ishikawa M, Naito M, Hashimoto Y . Design, synthesis and biological evaluation of nuclear receptor-degradation inducers . Bioorganic & Medicinal Chemistry . 19 . 22 . 6768–78 . November 2011 . 22014751 . 10.1016/j.bmc.2011.09.041 .
  14. Web site: Connecticut to support New Haven biotech to the tune of $4.25 million . New Haven Register . 2013-09-26. 2016-05-13.
  15. Web site: Scientist wants to hijack cells' tiny garbage trucks to fight cancer . Boston Globe . 2016-05-21.
  16. Cecchini. Carlotta. Pannilunghi. Sara. Tardy. Sébastien. Scapozza. Leonardo. 2021. From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation. Frontiers in Chemistry. 9. 672267. 10.3389/fchem.2021.672267. 2296-2646. 8093871. 33959589. 2021FrCh....9..215C . free .
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  19. Schade. Markus. Scott. James S.. Hayhow. Thomas G.. Pike. Andy. Terstiege. Ina. Ahlqvist. Marie. Johansson. Johan R.. Diene. Coura R.. Fallan. Charlene. Balazs. Amber Y. S.. Chiarparin. Elisabetta. Wilson. David. July 2024. Structural and Physicochemical Features of Oral PROTACs. Journal of Medicinal Chemistry. 10.1021/acs.jmedchem.4c01017. 0022-2623 .
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