Proteolysis targeting chimera

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A proteolysis targeting chimera (PROTAC) is a heterobifunctional small molecule composed of two active domains and a linker capable of removing specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. 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 by 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.[1]

Initially described by Kathleen Sakamoto, Craig Crews and Ray Deshaies in 2001,[2] the PROTAC technology has been applied by a number of drug discovery labs using various E3 ligases,[3] including pVHL,[4][5][6] Mdm2,[7] beta-TrCP1,[2] cereblon,[8][9] and c-IAP1.[10] Yale University licensed the PROTAC technology to Arvinas in 2013–14.[11][12]


Protacs achieve degradation through "hijacking" the cell's Ubiquitin–Proteosome system (UPS).[13] The UPS consists of an E1 activating enzyme which conjugates to an E2 enzyme transferring a ubiquitin molecule to the E2. E2 then binds to the E3 ligase in a complex which can then recognize target proteins for subsequent ubiquitin tagging and degradation by the 26S proteosome.


  1. ^ Cermakova K, Hodges HC (August 2018). "Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation". Molecules. 23 (8): 1958. doi:10.3390/molecules23081958. PMC 6102721. PMID 30082609.
  2. ^ a b Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ (July 2001). "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. Bibcode:2001PNAS...98.8554S. doi:10.1073/pnas.141230798. PMC 37474. PMID 11438690.
  3. ^ Chi KR (May 2016). "Drug developers delve into the cell's trash-disposal machinery". Nature Reviews. Drug Discovery. 15 (5): 295–7. doi:10.1038/nrd.2016.86. PMID 27139985.
  4. ^ Zengerle M, Chan KH, Ciulli A (August 2015). "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4". ACS Chemical Biology. 10 (8): 1770–7. doi:10.1021/acschembio.5b00216. PMC 4548256. PMID 26035625.
  5. ^ Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al. (August 2015). "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature Chemical Biology. 11 (8): 611–7. doi:10.1038/nchembio.1858. PMC 4629852. PMID 26075522.
  6. ^ Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM (August 2015). "HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins". ACS Chemical Biology. 10 (8): 1831–7. doi:10.1021/acschembio.5b00442. PMC 4629848. PMID 26070106.
  7. ^ Schneekloth AR, Pucheault M, Tae HS, Crews CM (November 2008). "Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics". Bioorganic & Medicinal Chemistry Letters. 18 (22): 5904–8. doi:10.1016/j.bmcl.2008.07.114. PMC 3175619. PMID 18752944.
  8. ^ 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. doi:10.1016/j.chembiol.2015.05.009. PMC 4475452. PMID 26051217.
  9. ^ 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. doi:10.1126/science.aab1433. PMC 4937790. PMID 25999370.
  10. ^ Itoh Y, Kitaguchi R, Ishikawa M, Naito M, Hashimoto Y (November 2011). "Design, synthesis and biological evaluation of nuclear receptor-degradation inducers". Bioorganic & Medicinal Chemistry. 19 (22): 6768–78. doi:10.1016/j.bmc.2011.09.041. PMID 22014751.
  11. ^ "Connecticut to support New Haven biotech to the tune of $4.25 million". New Haven Register. 2013-09-26. Retrieved 2016-05-13.
  12. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. Retrieved 2016-05-21.
  13. ^ Bondeson, Daniel P.; Crews, Craig M. (2017-01-06). "Targeted Protein Degradation by Small Molecules". Annual Review of Pharmacology and Toxicology. 57: 107–123. doi:10.1146/annurev-pharmtox-010715-103507. ISSN 0362-1642. PMC 5586045. PMID 27732798.