Proteolysis targeting chimera

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 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.[3][4]

Initially described by Kathleen Sakamoto, Craig Crews and Ray Deshaies in 2001,[5] the PROTAC technology has been applied by a number of 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]

  1. ^ Ishoey M, Chorn S, Singh N, Jaeger MG, Brand M, Paulk J, et al. (March 2018). "Translation Termination Factor GSPT1 Is a Phenotypically Relevant Off-Target of Heterobifunctional Phthalimide Degraders". ACS Chemical Biology. 13 (3): 553–560. doi:10.1021/acschembio.7b00969. PMID 29356495.
  2. ^ Luh LM, Scheib U, Juenemann K, Wortmann L, Brands M, Cromm PM (September 2020). "Prey for the Proteasome: Targeted Protein Degradation-A Medicinal Chemist's Perspective". Angewandte Chemie. 59 (36): 15448–15466. doi:10.1002/anie.202004310. PMC 7496094. PMID 32428344.
  3. ^ 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.
  4. ^ Noblejas-López MD, Tébar-García D, López-Rosa R, Alcaraz-Sanabria A, Cristóbal-Cueto P, Pinedo-Serrano A, et al. (October 2023). "TACkling Cancer by Targeting Selective Protein Degradation". Pharmaceutics. 15 (10): 2442. doi:10.3390/pharmaceutics15102442. PMC 10610449. PMID 37896202.
  5. ^ 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): 8554–8559. Bibcode:2001PNAS...98.8554S. doi:10.1073/pnas.141230798. PMC 37474. PMID 11438690.
  6. ^ Chi KR (May 2016). "Drug developers delve into the cell's trash-disposal machinery". Nature Reviews. Drug Discovery. 15 (5): 295–297. doi:10.1038/nrd.2016.86. PMID 27139985. S2CID 34652880.
  7. ^ Zengerle M, Chan KH, Ciulli A (August 2015). "Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4". ACS Chemical Biology. 10 (8): 1770–1777. doi:10.1021/acschembio.5b00216. PMC 4548256. PMID 26035625.
  8. ^ 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): 611–617. doi:10.1038/nchembio.1858. PMC 4629852. PMID 26075522.
  9. ^ Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, et al. (August 2015). "HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins". ACS Chemical Biology. 10 (8): 1831–1837. doi:10.1021/acschembio.5b00442. PMC 4629848. PMID 26070106.
  10. ^ Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al. (June 2015). "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4". Chemistry & Biology. 22 (6): 755–763. doi:10.1016/j.chembiol.2015.05.009. PMC 4475452. PMID 26051217.
  11. ^ Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al. (June 2015). "DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation". Science. 348 (6241): 1376–1381. doi:10.1126/science.aab1433. PMC 4937790. PMID 25999370.
  12. ^ 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): 5904–5908. doi:10.1016/j.bmcl.2008.07.114. PMC 3175619. PMID 18752944.
  13. ^ Zhang X, Luukkonen LM, Eissler CL, Crowley VM, Yamashita Y, Schafroth MA, et al. (April 2021). "DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras". Journal of the American Chemical Society. 143 (13): 5141–5149. doi:10.1021/jacs.1c00990. PMC 8309050. PMID 33783207.
  14. ^ Xue G, Xie J, Hinterndorfer M, Cigler M, Dötsch L, Imrichova H, et al. (November 2023). "Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype". Nature Communications. 14 (1): 7908. Bibcode:2023NatCo..14.7908X. doi:10.1038/s41467-023-43657-6. PMC 10689823. PMID 38036533.
  15. ^ a b c Ocaña A, Pandiella A (September 2020). "Proteolysis targeting chimeras (PROTACs) in cancer therapy". Journal of Experimental & Clinical Cancer Research. 39 (1): 189. doi:10.1186/s13046-020-01672-1. PMC 7493969. PMID 32933565.
  16. ^ 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): 6768–6778. 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. Retrieved 2016-05-13.
  18. ^ "Scientist wants to hijack cells' tiny garbage trucks to fight cancer". Boston Globe. Retrieved 2016-05-21.
  19. ^ Cite error: The named reference Schneider_2021 was invoked but never defined (see the help page).
  20. ^ Cecchini C, Pannilunghi S, Tardy S, Scapozza L (2021). "From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation". Frontiers in Chemistry. 9: 672267. Bibcode:2021FrCh....9..215C. doi:10.3389/fchem.2021.672267. PMC 8093871. PMID 33959589.
  21. ^ "A Study of ARV-766 Given by Mouth in Men With Metastatic Prostate Cancer". ClinicalTrialsGov. NCT05067140.