Proteolysis targeting chimera

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A proteolysis targeting chimera (PROTAC) is a two-headed molecule capable of removing unwanted proteins by inducing selective intracellular proteolysis. PROTACs consist of two linked protein binding molecules, one capable of engaging an E3 ubiquitin ligase and the other to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Initially described by Craig Crews and Ray Deshaies in 2001,[1] the PROTAC technology has been applied by a number of drug discovery labs to various E3 ligases,[2] including pVHL,[3][4][5] MDM2,[6] beta-TrCP1,[1] cereblon,[7][8] and c-IAP1.[9] Yale University licensed the PROTAC technology to Arvinas in 2013-14.[10][11]


  1. ^ a b Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ (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. doi:10.1073/pnas.141230798. PMC 37474Freely accessible. PMID 11438690. 
  2. ^ Chi KR (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. 
  3. ^ Zengerle M, Chan K-H, Ciulli A (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 4548256Freely accessible. PMID 26035625. 
  4. ^ 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 (2015). "Catalytic in vivo protein knockdown by small-molecule PROTACs". Nature Chemical Biology. 11 (8): 611–7. doi:10.1038/nchembio.1858. PMC 4629852Freely accessible. PMID 26075522. 
  5. ^ Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM (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 4629848Freely accessible. PMID 26070106. 
  6. ^ Schneekloth AR, Pucheault M, Tae HS, Crews CM (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 3175619Freely accessible. PMID 18752944. 
  7. ^ Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM (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 4475452Freely accessible. PMID 26051217. 
  8. ^ Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE (2015). "Phthalimide conjugation as a strategy for in vivo target protein degradation". Science. 348 (6241): 1376–81. doi:10.1126/science.aab1433. PMC 4937790Freely accessible. PMID 25999370. 
  9. ^ Itoh Y, Kitaguchi R, Ishikawa M, Naito M, Hashimoto Y (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. 
  10. ^ "Connecticut to support New Haven biotech to the tune of $4.25 million". New Haven Register. Retrieved 2016-05-13. 
  11. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. Retrieved 2016-05-21.