PROTAC: A Novel Drug Delivery Technology for Targeting Proteins in
Cancer Cells

Rajni      Bala; Rakesh   Kumar   Sindhu; Reecha      Madaan; Shantanu   Kumar   Yadav

doi:10.2174/1570163820666221031124612

Abstract

The treatment measures of malignant carcinomas are most important for human health. In recent years the use of targeted therapy based on small molecule compounds and identical immunoglobulin has been the most frequently used tool to combat cancerous cells. But there are still several limitations in their clinical development and applications, including their ability to bind multiple molecular target sites, both cell surface receptors and intracellular proteins, promoting a greater risk of toxicity. PROTAC is a novel technology that maintains a balance between protein synthesis and degradation and uses molecules instead of conventional enzyme inhibitors, containing two active domains and a linker to destroy unwanted selective protein (like kinase, skeleton protein and regulatory protein). PROTACs are heterobifunctional nano molecules with a size range of about 10 nanometres that eliminate the protein complexes formed by protein-protein interaction through large and flat surfaces generally defined as “undruggable” in conventional drug delivery systems, which include around 85% of proteins present in humans, suggesting their wide application in the field of drug development. Such peptide-based PROTACs have successfully shown targets' destruction in cultured cells (e.g., MetAP-2, and FKBP12^F36V, receptors for estrogens and androgen). However, some obstacles prevent this technology from transferring from the laboratory to its actual clinical utility, such as delivery system and bioavailability. The scope of the presented review is to give an overview of novel PROTAC technology with its limitations, advantages, mechanism of action, and development of photocontrolled PROTACs and to summarize its futuristic approach to targeting proteins in cancer cells.

Graphical Abstract

[1]
Veggiani G, Gerpe MCR, Sidhu SS, Zhang W. Emerging drug development technologies targeting ubiquitination for cancer therapeutics. Pharmacol Ther  2019; 199(199): 139-54.
 [http://dx.doi.org/10.1016/j.pharmthera.2019.03.003] [PMID: 30851297]

[2]
Wang P, Zhou J. Proteolysis Targeting Chimera (PROTAC): A paradigm-shifting approach in small molecule drug discovery. Curr Top Med Chem  2018; 18(16): 1354-6.
 [http://dx.doi.org/10.2174/1568026618666181010101922] [PMID: 30306871]

[3]
Lai AC, Crews CM. Induced protein degradation: An emerging drug discovery paradigm. Nat Rev Drug Discov  2017; 16(2): 101-14.
 [http://dx.doi.org/10.1038/nrd.2016.211] [PMID: 27885283]

[4]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell  2011; 144(5): 646-74.
 [http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]

[5]
Inobe T, Matouschek A. Paradigms of protein degradation by the proteasome. Curr Opin Struct Biol  2014; 24: 156-64.
 [http://dx.doi.org/10.1016/j.sbi.2014.02.002] [PMID: 24632559]

[6]
An S, Fu L. Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs. EBioMedicine  2018; 36: 553-62.
 [http://dx.doi.org/10.1016/j.ebiom.2018.09.005] [PMID: 30224312]

[7]
Bushweller JH. Targeting transcription factors in cancer - From undruggable to reality. Nat Rev Cancer  2019; 19(11): 611-24.
 [http://dx.doi.org/10.1038/s41568-019-0196-7] [PMID: 31511663]

[8]
Sakamoto KM. Protacs for treatment of cancer. Pediatr Res  2010; 67(5): 505-8.
 [http://dx.doi.org/10.1203/PDR.0b013e3181d35017] [PMID: 20075761]

[9]
Zhang L, Riley GB, Vijay P, Shen Y. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic altera-tions in core components of E3 ligase complexes. Mol Cancer Ther  2019; 18(7): 1302-11.
 [http://dx.doi.org/10.1158/1535-7163.MCT-18-1129] [PMID: 31064868]

[10]
Gu S, Cui D, Chen X, Xiong X, Zhao Y. PROTACs: An emerging targeting technique for protein degradation in drug discovery. BioEssays  2018; 40(4): 1700247.
 [http://dx.doi.org/10.1002/bies.201700247] [PMID: 29473971]

[11]
Paiva SL, Crews CM. Targeted protein degradation: Elements of PROTAC design. Curr Opin Chem Biol  2019; 50: 111-9.
 [http://dx.doi.org/10.1016/j.cbpa.2019.02.022] [PMID: 31004963]

[12]
Toure M, Crews CM. Small-molecule PROTACS: New approaches to protein degradation. Angew Chem Int Ed  2016; 55(6): 1966-73.
 [http://dx.doi.org/10.1002/anie.201507978] [PMID: 26756721]

[13]
Lazo JS, Sharlow ER. Drugging undruggable molecular cancer targets. Annu Rev Pharmacol Toxicol  2016; 56(1): 23-40.
 [http://dx.doi.org/10.1146/annurev-pharmtox-010715-103440] [PMID: 26527069]

[14]
Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: Treating cancer with specificity. Eur J Pharmacol  2018; 834: 188-96.
 [http://dx.doi.org/10.1016/j.ejphar.2018.07.034] [PMID: 30031797]

[15]
Pettersson M, Crews CM. PROteolysis Targeting Chimeras (PROTACs)-Past, present and future. Drug Discov Today Technol  2019; 31: 15-27.
 [http://dx.doi.org/10.1016/j.ddtec.2019.01.002] [PMID: 31200855]

[16]
Farnaby W, Koegl M, Roy MJ, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol  2019; 15(7): 672-80.
 [http://dx.doi.org/10.1038/s41589-019-0294-6] [PMID: 31178587]

[17]
Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted protein degradation: Expanding the toolbox. Nat Rev Drug Discov  2019; 18(12): 949-63.
 [http://dx.doi.org/10.1038/s41573-019-0047-y] [PMID: 31666732]

[18]
Nalawansha DA, Crews CM. PROTACs: An emerging therapeutic modality in precision medicine. Cell Chem Biol  2020; 27(8): 998-1014.
 [http://dx.doi.org/10.1016/j.chembiol.2020.07.020] [PMID: 32795419]

[19]
Wu HQ, Baker D, Ovaa H. Small molecules that target the ubiquitin system. Biochem Soc Trans  2020; 48(2): 479-97.
 [http://dx.doi.org/10.1042/BST20190535] [PMID: 32196552]

[20]
Murciano GYR, Taylor BS, Hyman DM, Schram AM. Toward a more precise future for oncology. Cancer Cell  2020; 37(4): 431-42.
 [http://dx.doi.org/10.1016/j.ccell.2020.03.014] [PMID: 32289268]

[21]
Roos MP, Sistonen L. The ubiquitin-proteasome pathway. Ann Med  2004; 36(4): 285-95.
 [http://dx.doi.org/10.1080/07853890310016324] [PMID: 15224655]

[22]
Bondeson DP, Smith BE, Burslem GM, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol  2018; 25(1): 78-87.e5.
 [http://dx.doi.org/10.1016/j.chembiol.2017.09.010] [PMID: 29129718]

[23]
Churcher I. Protac-induced protein degradation in drug discovery: Breaking the rules or just making new ones. J Med Chem  2018; 61(2): 444-52.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b01272] [PMID: 29144739]

[24]
Maniaci C, Hughes SJ, Testa A, et al. Homo-PROTACs: Bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat Commun  2017; 8(1): 830.
 [http://dx.doi.org/10.1038/s41467-017-00954-1] [PMID: 29018234]

[25]
Zou Y, Ma D, Wang Y. The PROTAC technology in drug development. Cell Biochem Funct  2019; 37(1): 21-30.
 [http://dx.doi.org/10.1002/cbf.3369] [PMID: 30604499]

[26]
Edmondson SD, Yang B, Fallan C. Proteolysis Targeting Chimeras (PROTACs) in ‘beyond rule-of-five’chemical space: Recent progress and future challenges. Bioorganic Med. Chem. Lett. 2019; 29(13):1555-64.

[27]
Han X, Wang C, Qin C, et al. Discovery of ARD-69 as a highly potent Proteolysis Targeting Chimera (PROTAC) degrader of Androgen Receptor (AR) for the treatment of prostate cancer. J Med Chem  2019; 62(2): 941-64.
 [http://dx.doi.org/10.1021/acs.jmedchem.8b01631] [PMID: 30629437]

[28]
Gadd MS, Testa A, Lucas X, et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol  2017; 13(5): 514-21.
 [http://dx.doi.org/10.1038/nchembio.2329] [PMID: 28288108]

[29]
Wang Y, Jiang X, Feng F, Liu W, Sun H. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B  2020; 10(2): 207-38.
 [http://dx.doi.org/10.1016/j.apsb.2019.08.001] [PMID: 32082969]

[30]
Lu M, Liu T, Jiao Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur J Med Chem  2018; 146: 251-9.
 [http://dx.doi.org/10.1016/j.ejmech.2018.01.063] [PMID: 29407955]

[31]
Demasi M, Da Cunha FM. The physiological role of the free 20S proteasome in protein degradation: A critical review. Biochim Biophys Acta, Gen Subj  2018; 1862(12): 2948-54.
 [http://dx.doi.org/10.1016/j.bbagen.2018.09.009] [PMID: 30297324]

[32]
Deshaies RJ. Prime time for PROTACs. Nat Chem Biol  2015; 11(9): 634-5.
 [http://dx.doi.org/10.1038/nchembio.1887] [PMID: 26284668]

[33]
Sun X, Gao H, Yang Y, et al. PROTACs: Great opportunities for academia and industry. Signal Transduct Target Ther  2019; 4(1): 64.
 [http://dx.doi.org/10.1038/s41392-019-0101-6] [PMID: 31885879]

[34]
Burslem GM, Smith BE, Lai AC, et al. The advantages of targeted protein degradation over inhibition: An RTK case study. Cell Chem Biol  2018; 25(1): 67-77.e3.
 [http://dx.doi.org/10.1016/j.chembiol.2017.09.009] [PMID: 29129716]

[35]
Konstantinidou M, Li J, Zhang B, et al. PROTACs-a game-changing technology. Expert Opin Drug Discov  2019; 14(12): 1255-68.
 [http://dx.doi.org/10.1080/17460441.2019.1659242] [PMID: 31538491]

[36]
Ma D, Zou Y, Chu Y, et al. A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer. Theranostics  2020; 10(8): 3708-21.
 [http://dx.doi.org/10.7150/thno.41677] [PMID: 32206117]

[37]
Au YZ, Wang T, Sigua LH, Qi J. Peptide-based PROTAC: The predator of pathological proteins. Cell Chem Biol  2020; 27(6): 637-9.
 [http://dx.doi.org/10.1016/j.chembiol.2020.06.002] [PMID: 32559499]

[38]
Liao H, Li X, Zhao L, et al. A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer. Cell Discov  2020; 6(1): 35.
 [http://dx.doi.org/10.1038/s41421-020-0171-1] [PMID: 32550000]

[39]
Pei H, Peng Y, Zhao Q, Chen Y. Small molecule PROTACs: An emerging technology for targeted therapy in drug discovery. RSC Advances  2019; 9(30): 16967-76.
 [http://dx.doi.org/10.1039/C9RA03423D] [PMID: 35519875]

[40]
Schneekloth AR, Pucheault M, Tae HS, Crews CM. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett  2008; 18(22): 5904-8.
 [http://dx.doi.org/10.1016/j.bmcl.2008.07.114] [PMID: 18752944]

[41]
Demizu Y, Shibata N, Hattori T, et al. Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Bioorg Med Chem Lett  2016; 26(20): 4865-9.
 [http://dx.doi.org/10.1016/j.bmcl.2016.09.041] [PMID: 27666635]

[42]
Itoh Y, Kitaguchi R, Ishikawa M, Naito M, Hashimoto Y. Design, synthesis and biological evaluation of nuclear receptor-degradation inducers. Bioorg Med Chem  2011; 19(22): 6768-78.
 [http://dx.doi.org/10.1016/j.bmc.2011.09.041] [PMID: 22014751]

[43]
Okuhira K, Demizu Y, Hattori T, et al. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci  2013; 104(11): 1492-8.
 [http://dx.doi.org/10.1111/cas.12272] [PMID: 23992566]

[44]
Garber K. The PROTAC gold rush. Nat Biotechnol  2022; 40(1): 12-6.
 [http://dx.doi.org/10.1038/s41587-021-01173-2] [PMID: 34907403]

[45]
Jin J, Wu Y, Chen J, et al. The peptide PROTAC modality: A novel strategy for targeted protein ubiquitination. Theranostics  2020; 10(22): 10141-53.
 [http://dx.doi.org/10.7150/thno.46985] [PMID: 32929339]

[46]
Jiang Y, Deng Q, Zhao H, et al. Development of stabilized peptide-based PROTACs against estrogen receptor α. ACS Chem Biol  2018; 13(3): 628-35.
 [http://dx.doi.org/10.1021/acschembio.7b00985] [PMID: 29271628]

[47]
Rodriguez GA, Cyrus K, Salcius M, et al. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene  2008; 27(57): 7201-11.
 [http://dx.doi.org/10.1038/onc.2008.320] [PMID: 18794799]

[48]
Martín AP, Xiao X. PROTACs to address the challenges facing small molecule inhibitors. Eur J Med Chem  2021; 210: 112993.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112993] [PMID: 33189436]

[49]
Iwakuma T, Lozano G. MDM2, an introduction. Mol Cancer Res  2003; 1(14): 993-1000.
 [PMID: 14707282]

[50]
Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res  2019; 79(1): 251-62.
 [http://dx.doi.org/10.1158/0008-5472.CAN-18-2918] [PMID: 30385614]

[51]
Li Y, Yang J, Aguilar A, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumour regression. J Med Chem  2019; 62(2): 448-66.
 [http://dx.doi.org/10.1021/acs.jmedchem.8b00909] [PMID: 30525597]

[52]
Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer  2019; 125(21): 3714-28.
 [http://dx.doi.org/10.1002/cncr.32345] [PMID: 31318440]

[53]
Vicente ATS, Salvador JAR. MDM2-based Proteolysis-Targeting Chimeras (PROTACs): An innovative drug strategy for cancer treatment. Int J Mol Sci  2022; 23(19): 11068.
 [http://dx.doi.org/10.3390/ijms231911068] [PMID: 36232374]

[54]
Zhang X, Thummuri D, Liu X, et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur J Med Chem  2020; 192: 112186.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112186] [PMID: 32145645]

[55]
Zhang H, Li G, Zhang Y, et al. Targeting BET proteins with a PROTAC molecule elicits potent anticancer activity in HCC cells. Front Oncol  2020; 9: 1471.
 [http://dx.doi.org/10.3389/fonc.2019.01471] [PMID: 31993368]

[56]
Lim SL, Damnernsawad A, Shyamsunder P, et al. Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations. Haematologica  2019; 104(6): 1209-20.
 [http://dx.doi.org/10.3324/haematol.2018.201483] [PMID: 30606790]

[57]
Sekine K, Takubo K, Kikuchi R, et al. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J Biol Chem  2008; 283(14): 8961-8.
 [http://dx.doi.org/10.1074/jbc.M709525200] [PMID: 18230607]

[58]
Uhrig M, Brechlin P, Jahn O, et al. Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Aβ42 reduces their differentiation potential. BMC Med  2008; 6(1): 38-49.
 [http://dx.doi.org/10.1186/1741-7015-6-38] [PMID: 19087254]

[59]
Gupta A, Williams BRG, Hanash SM, Rawwas J. Cellular retinoic acid-binding protein II is a direct transcriptional target of MycN in neuroblastoma. Cancer Res  2006; 66(16): 8100-8.
 [http://dx.doi.org/10.1158/0008-5472.CAN-05-4519] [PMID: 16912187]

[60]
Gupta A, Kessler P, Rawwas J, Williams BRG. Regulation of CRABP-II expression by MycN in Wilms tumor. Exp Cell Res  2008; 314(20): 3663-8.
 [http://dx.doi.org/10.1016/j.yexcr.2008.09.029] [PMID: 18955045]

[61]
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science  2010; 327(5971): 1345-50.
 [http://dx.doi.org/10.1126/science.1177319] [PMID: 20223979]

[62]
Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science  2014; 343(6168): 301-5.
 [http://dx.doi.org/10.1126/science.1244851] [PMID: 24292625]

[63]
Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science  2014; 343(6168): 305-9.
 [http://dx.doi.org/10.1126/science.1244917] [PMID: 24292623]

[64]
Kortüm KM, Zhu YX, Shi CX, Jedlowski P, Stewart AK. Cereblon binding molecules in multiple myeloma. Blood Rev  2015; 29(5): 329-34.
 [http://dx.doi.org/10.1016/j.blre.2015.03.003] [PMID: 25843596]

[65]
Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature  2014; 512(7512): 49-53.
 [http://dx.doi.org/10.1038/nature13527] [PMID: 25043012]

[66]
Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell  2011; 146(6): 904-17.
 [http://dx.doi.org/10.1016/j.cell.2011.08.017] [PMID: 21889194]

[67]
Buckley DL, Van Molle I, Gareiss PC, et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J Am Chem Soc  2012; 134(10): 4465-8.
 [http://dx.doi.org/10.1021/ja209924v] [PMID: 22369643]

[68]
Buckley DL, Gustafson JL, Van Molle I, et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew Chem Int Ed  2012; 51(46): 11463-7.
 [http://dx.doi.org/10.1002/anie.201206231] [PMID: 23065727]

[69]
Van Molle I, Thomann A, Buckley DL, et al. Dissecting fragment-based lead discovery at the von Hippel-Lindau protein: Hypoxia inducible factor 1α protein-protein interface. Chem Biol  2012; 19(10): 1300-12.
 [http://dx.doi.org/10.1016/j.chembiol.2012.08.015] [PMID: 23102223]

[70]
Bondeson DP, Mares A, Smith IED, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol  2015; 11(8): 611-7.
 [http://dx.doi.org/10.1038/nchembio.1858] [PMID: 26075522]

[71]
Wan Y, Liu T, Hou X, Dun Y, Guan P, Fang H. Antagonists of IAP proteins: Novel anti-tumor agents. Curr Med Chem  2014; 21(34): 3877-92.
 [http://dx.doi.org/10.2174/0929867321666140826115258] [PMID: 25174926]

[72]
Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov  2012; 11(2): 109-24.
 [http://dx.doi.org/10.1038/nrd3627] [PMID: 22293567]

[73]
Wan Y, Yan C, Gao H, Liu T. Small-molecule PROTACs: novel agents for cancer therapy. Future Med Chem  2020; 12(10): 915-38.
 [http://dx.doi.org/10.4155/fmc-2019-0340] [PMID: 32270707]

[74]
Eldeeb MA, Zorca CE, Fahlman RP. Targeting cancer cells via N-degron-based PROTACs. Endocrinology  2020; 161(12): bqaa185.
 [http://dx.doi.org/10.1210/endocr/bqaa185] [PMID: 33159513]

[75]
Eldeeb MA. N-terminal-dependent protein degradation and targeting cancer cells. Anticancer Agents Med Chem  2020; 21(2): 231-6.
 [http://dx.doi.org/10.2174/1871520620666200819112632] [PMID: 32814541]

[76]
Ocaña A, Pandiella A. Proteolysis Targeting Chimeras (PROTACs) in cancer therapy. J Exp Clin Cancer Res  2020; 39(1): 189.
 [http://dx.doi.org/10.1186/s13046-020-01672-1] [PMID: 32933565]

[77]
Burslem GM, Schultz AR, Bondeson DP, et al. Targeting BCR-ABL1 in chronic myeloid leukaemia by PROTAC-mediated targeted protein degradation. Cancer Res  2019; 79(18): 4744-53.
 [http://dx.doi.org/10.1158/0008-5472.CAN-19-1236] [PMID: 31311809]

[78]
White ME, Fenger JM, Carson WE III. Emerging roles of and therapeutic strategies targeting BRD4 in cancer. Cell Immunol  2019; 337: 48-53.
 [http://dx.doi.org/10.1016/j.cellimm.2019.02.001] [PMID: 30832981]

[79]
Noblejas LMM, Nieto JC, Burgos M, et al. Activity of BET-Proteolysis Targeting Chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res  2019; 38(1): 383.
 [http://dx.doi.org/10.1186/s13046-019-1387-5] [PMID: 30606223]

[80]
Testa A, Hughes SJ, Lucas X, Wright JE, Ciulli A. Structure-based design of a macrocyclic PROTAC. Angew Chem Int Ed  2020; 59(4): 1727-34.
 [http://dx.doi.org/10.1002/anie.201914396] [PMID: 31746102]

[81]
Huang HT, Dobrovolsky D, Paulk J, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol  2018; 25(1): 88-99.e6.
 [http://dx.doi.org/10.1016/j.chembiol.2017.10.005] [PMID: 29129717]

[82]
Tinworth CP, Lithgow H, Dittus L, et al. PROTAC-mediated degradation of Bruton’s tyrosine kinase is inhibited by covalent binding. ACS Chem Biol  2019; 14(3): 342-7.
 [http://dx.doi.org/10.1021/acschembio.8b01094] [PMID: 30807093]

[83]
Papatzimas JW, Gorobets E, Maity R, et al. From inhibition to degradation: Targeting the antiapoptotic protein Myeloid Cell Leukemia 1 (MCL1). J Med Chem  2019; 62(11): 5522-40.
 [http://dx.doi.org/10.1021/acs.jmedchem.9b00455] [PMID: 31117518]

[84]
Chen Q, Lv J, Yang W, et al. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics  2019; 9(22): 6424-42.
 [http://dx.doi.org/10.7150/thno.35528] [PMID: 31588227]

[85]
Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y. Proteolysis-Targeting Chimeras (PROTACs) in cancer therapy. Mol Cancer  2022; 21(1): 99.
 [http://dx.doi.org/10.1186/s12943-021-01434-3] [PMID: 35410300]

[86]
Liu Q, Tu G, Hu Y, et al. Discovery of BP3 as an efficacious Proteolysis Targeting Chimera (PROTAC) degrader of HSP90 for treating breast cancer. Eur J Med Chem  2022; 228: 114013.
 [http://dx.doi.org/10.1016/j.ejmech.2021.114013] [PMID: 34864330]

[87]
Wang C, Zheng C, Wang H, Zhang L, Liu Z, Xu P. The state of the art of PROTAC technologies for drug discovery. Eur J Med Chem  2022; 235: 114290.
 [http://dx.doi.org/10.1016/j.ejmech.2022.114290] [PMID: 35307618]

[88]
Benowitz AB, Scott SPT, Harling JD. Challenges and opportunities for in vivo PROTAC delivery. Future Med Chem  2022; 14(3): 119-21.
 [http://dx.doi.org/10.4155/fmc-2021-0223] [PMID: 34528453]

[89]
Qi SM, Dong J, Xu ZY, Cheng XD, Zhang WD, Qin JJ. PROTAC: An effective targeted protein degradation strategy for cancer therapy. Front Pharmacol  2021; 12: 692574.
 [http://dx.doi.org/10.3389/fphar.2021.692574] [PMID: 34025443]

[90]
Flanagan J, Qian Y, Gough S, et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer. Cancer Res 2019; 79: P5–P04-18. 
 [http://dx.doi.org/10.1158/1538-7445.SABCS18-P5-04-18]

[91]
Zhou Q, Kyazike J, Boudanova E, et al. Site-specific antibody conjugation to engineered double cysteine residues. Pharmaceuticals  2021; 14(7): 672.
 [http://dx.doi.org/10.3390/ph14070672]

[92]
Maneiro M, Forte N, Shchepinova MM, et al. Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem Biol  2020; 15(6): 1306-12.
 [http://dx.doi.org/10.1021/acschembio.0c00285] [PMID: 32338867]

[93]
Xue G, Wang K, Zhou D, Zhong H, Pan Z. Light-induced protein degradation with photocaged PROTACs. J Am Chem Soc  2019; 141(46): 18370-4.
 [http://dx.doi.org/10.1021/jacs.9b06422] [PMID: 31566962]

[94]
Li W, Elhassan RM, Fang H, Hou X. Photopharmacology-based small-molecule proteolysis targeting chimeras: Optical control of protein degradation. Future Med Chem  2020; 12(22): 1991-3.
 [http://dx.doi.org/10.4155/fmc-2020-0210] [PMID: 33054433]

[95]
Pfaff P, Samarasinghe KTG, Crews CM, Carreira EM. Reversible spatiotemporal control of induced protein degradation by bistable photo PROTACs. ACS Cent Sci  2019; 5(10): 1682-90.
 [http://dx.doi.org/10.1021/acscentsci.9b00713] [PMID: 31660436]

[96]
Velema WA, Szymanski W, Feringa BL. Photopharmacology: Beyond proof of principle. J Am Chem Soc  2014; 136(6): 2178-91.
 [http://dx.doi.org/10.1021/ja413063e] [PMID: 24456115]

[97]
Troup RI, Fallan C, Baud MGJ. Current strategies for the design of PROTAC linkers: A critical review. Explor Target Anti-tumor Ther  2020; 1(5): 273-312.
 [http://dx.doi.org/10.37349/etat.2020.00018] [PMID: 36046485]

[98]
Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharmacol Ther  2017; 174: 138-44.
 [http://dx.doi.org/10.1016/j.pharmthera.2017.02.027] [PMID: 28223226]

[99]
Zhenyi HU, Craig MC. Recent developments in PROTAC-mediated protein degradation: From bench to clinic. ChemBioChem  2022; 23(2): e202100270.
 [http://dx.doi.org/10.1002/cbic.202100270] [PMID: 34494353]

[100]
Yang G, Zhong H, Xia X, Qi Z, Wang C, Li S. Potential application of Proteolysis Targeting Chimera (PROTAC) modification technology in natural products for their targeted protein degradation. Food Sci Hum Wellness  2022; 11(2): 199-207.
 [http://dx.doi.org/10.1016/j.fshw.2021.11.001]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570163820666221031124612	Print ISSN 1570-1638
Publisher Name Bentham Science Publisher	Online ISSN 1875-6220

Current Drug Discovery Technologies

PROTAC: A Novel Drug Delivery Technology for Targeting Proteins in Cancer Cells

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract