PROTAC technology for prostate cancer treatment

Abstract

Prostate cancer (PrCa) is the most prevalent urogenital cancer affecting men. PrCa is marked by uncontrolled cellular growth that leads to abnormal enlargement of the prostate gland. The metastatic spread of PrCa is the primary cause of mortality, causing cancer cell dissemination to distant sites, such as bones, the pelvis, and various visceral organs. Key contributors to PrCa progression include genetic mutations, elevated androgen receptor expression, gene amplification, and the rise of androgen receptor splice variants. Although androgen deprivation therapy remains the mainstay for early-stage PrCa treatment, efficacy is temporary because many cases advance to castration-resistant PrCa (CRPC), presenting a significant therapeutic hurdle. This review explores key biomarkers for PrCa and the latest therapeutic strategies for CRPC with a particular focus on the innovative proteolysis-targeting chimera (PROTAC) technology. This approach offers a novel means of degrading target proteins and we discuss how PROTAC holds potential as effective strategies to combat resistance mechanisms in CRPC.

Keywords

Chemical biology / Cancer biology / PROTAC / Prostate cancer

References

[1] Denmeade SR, Isaacs JT: A History of Prostate Cancer Treatment. Nature Reviews. Cancer 2002, 2: 389-396.

[2] Wang Z, Wu S, Zhu C, Shen J: The Role of Ferroptosis in Esophageal Cancer. Cancer Cell International 2022, 22: 266.

[3] Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer Statistics, 2022. CA: A Cancer Journal for Clinicians 2022, 72: 7-33.

[4] Gandhi J, Afridi A, Vatsia S, Joshi G, Joshi G, Kaplan SA, et al.: The Molecular Biology of Prostate Cancer: Current Understanding and Clinical Implications. Prostate Cancer and Prostatic Diseases 2018, 21: 22-36.

[5] Kessel K, Seifert R, Weckesser M, Roll W, Humberg V, Schlack K, et al.: Molecular Analysis of Circulating Tumor Cells of Metastatic Castration-resistant Prostate Cancer Patients receiving (177)Lu-PSMA-617 Radioligand Therapy. Theranostics 2020, 10: 7645-7655.

[6] Liang J, Wang L, Poluben L, Nouri M, Arai S, Xie L, et al.: Androgen Receptor Splice Variant 7 Functions Independently of the Full Length Receptor in Prostate Cancer Cells. Cancer Letters 2021, 519: 172-184.

[7] Yap TA, Smith AD, Ferraldeschi R, Al-Lazikani B, Workman P, de Bono JS: Drug Discovery in Advanced Prostate Cancer: Translating Biology into Therapy. Nature Reviews. Drug Discovery 2016, 15: 699-718.

[8] Bekes M, Langley DR, Crews CM: PROTAC Targeted Protein Degraders: the Past is Prologue. Nature Reviews Drug Discovery 2022, 21: 181-200.

[9] He B, Kemppainen JA, Wilson EM: FXXLF and WXXLF Sequences Mediate the NH2-terminal Interaction with the Ligand Binding Domain of the Androgen Receptor. The Journal of Biological Chemistry 2000, 275: 22986-22994.

[10] Loy CJ, Sim KS, Yong EL: Filamin-A Fragment Localizes to the Nucleus to Regulate Androgen Receptor and Coactivator Functions. Proceedings of the National Academy of Sciences of the United States of America 2003, 100: 4562-4567.

[11] He B, Kemppainen JA, Voegel JJ, Gronemeyer H, Wilson EM: Activation Function 2 in the Human Androgen Receptor Ligand Binding Domain Mediates Interdomain Communication with the NH(2)-Terminal Domain. The Journal of Biological Chemistry 1999, 274: 37219-37225.

[12] Veldscholte J, Berrevoets CA, Zegers ND, van der Kwast TH, Grootegoed JA, Mulder E: Hormone-induced Dissociation of the Androgen Receptor-heat-shock Protein Complex: Use of a New Monoclonal Antibody to Distinguish Transformed from Nontransformed Receptors. Biochemistry 1992, 31: 7422-7430.

[13] Ozanne DM, Brady ME, Cook S, Gaughan L, Neal DE, Robson CN: Androgen Receptor Nuclear Translocation is Facilitated by the f-actin Cross-linking Protein Filamin. Molecular Endocrinology 2000, 14: 1618-1626.

[14] Cardozo CP, Michaud C, Ost MC, Fliss AE, Yang E, Patterson C, et al.: C-Terminal Hsp-interacting Protein Slows Androgen Receptor Synthesis and Reduces Its Rate of Degradation. Archives of Biochemistry and Biophysics 2003, 410: 134-140.

[15] Shatkina L, Mink S, Rogatsch H, Klocker H, Langer G, Nestl A, et al.: The Cochaperone Bag-1L Enhances Androgen Receptor Action via Interaction with the NH2-terminal Region of the Receptor. Molecular and Cellular Biology 2003, 23: 7189-7197.

[16] Liao G, Chen LY, Zhang A, Godavarthy A, Xia F, Ghosh JC, et al.: Regulation of Androgen Receptor Activity by the Nuclear Receptor Corepressor SMRT. The Journal of Biological Chemistry 2003, 278: 5052-5061.

[17] Cutress ML, Whitaker HC, Mills IG, Stewart M, Neal DE: Structural Basis for the Nuclear Import of the Human Androgen Receptor. Journal of Cell Science 2008, 121: 957-968.

[18] He B, Lee LW, Minges JT, Wilson EM: Dependence of Selective Gene Activation on the Androgen Receptor NH2- and COOH-terminal Interaction. The Journal of Biological Chemistry 2002, 277: 25631-25639.

[19] Lee YF, Shyr CR, Thin TH, Lin WJ, Chang C: Convergence of Two Repressors Through Heterodimer Formation of Androgen Receptor and Testicular Orphan Receptor-4: A Unique Signaling Pathway in the Steroid Receptor Superfamily. Proceedings of the National Academy of Sciences of the United States of America 1999, 96: 14724-14729.

[20] Rahman M, Miyamoto H, Chang C: Androgen Receptor Coregulators in Prostate Cancer: Mechanisms and Clinical Implications. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2004, 10: 2208-2219.

[21] Schaufele F, Carbonell X, Guerbadot M, Borngraeber S, Chapman MS, Ma AA, et al.: The Structural Basis of Androgen Receptor Activation: Intramolecular and Intermolecular Amino-carboxy Interactions. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 9802-9807.

[22] Zhou ZX, Sar M, Simental JA, Lane MV, Wilson EM: A Ligand-dependent Bipartite Nuclear Targeting Signal in the Human Androgen Receptor. Requirement for the DNA-binding Domain and Modulation by NH2-terminal and Carboxyl-terminal Sequences. The Journal of Biological Chemistry 1994, 269: 13115-13123.

[23] Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, et al.: Regulator of G-protein Signaling 2 (RGS2) Inhibits Androgen-independent Activation of Androgen Receptor in Prostate Cancer Cells. Oncogene 2006, 25: 3719-3734.

[24] Manin M, Baron S, Goossens K, Beaudoin C, Jean C, Veyssiere G, et al.: Androgen Receptor Expression is Regulated by the Phosphoinositide 3-kinase/Akt Pathway in Normal and Tumoral Epithelial Cells. The Biochemical Journal 2002, 366: 729-736.

[25] Scheid MP, Woodgett JR: PKB/AKT: Functional Insights from Genetic Models. Nature Reviews. Molecular Cell Biology 2001, 2: 760-768.

[26] Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C: From HER2/Neu Signal Cascade to Androgen Receptor and Its Coactivators: A Novel Pathway by Induction of Androgen Target Genes Through MAP Kinase in Prostate Cancer Cells. Proceedings of the National Academy of Sciences of the United States of America 1999, 96: 5458-5463.

[27] Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, et al.: Androgen Receptor Phosphorylation. Regulation and Identification of the Phosphorylation Sites. The Journal of Biological Chemistry 2002, 277: 29304-29314.

[28] Blok LJ, de Ruiter PE, Brinkmann AO: Forskolin-induced Dephosphorylation of the Androgen Receptor Impairs Ligand Binding. Biochemistry 1998, 37: 3850-3857.

[29] Rochette-Egly C: Nuclear Receptors: Integration of Multiple Signalling Pathways Through Phosphorylation. Cellular Signalling 2003, 15: 355-366.

[30] van Royen ME, Cunha SM, Brink MC, Mattern KA, Nigg AL, Dubbink HJ, et al.: Compartmentalization of Androgen Receptor Protein-protein Interactions in Living Cells. The Journal of Cell Biology 2007, 177: 63-72.

[31] Heinlein CA, Chang C: Androgen Receptor (AR) Coregulators: An Overview. Endocrine Reviews 2002, 23: 175-200.

[32] Powell SM, Christiaens V, Voulgaraki D, Waxman J, Claessens F, Bevan CL: Mechanisms of Androgen Receptor Signalling via Steroid Receptor Coactivator-1 in Prostate. Endocrine-Related Cancer 2004, 11: 117-130.

[33] Farla P, Hersmus R, Trapman J, Houtsmuller AB: Antiandrogens Prevent Stable DNA-binding of the Androgen Receptor. Journal of Cell Science 2005, 118: 4187-4198.

[34] Klokk TI, Kurys P, Elbi C, Nagaich AK, Hendarwanto A, Slagsvold T, et al.: Ligand-specific Dynamics of the Androgen Receptor at Its Response Element in Living Cells. Molecular and Cellular Biology 2007, 27: 1823-1843.

[35] Gaughan L, Logan IR, Neal DE, Robson CN: Regulation of Androgen Receptor and Histone Deacetylase 1 by Mdm2-mediated Ubiquitylation. Nucleic Acids Research 2005, 33: 13-26.

[36] Haelens A, Tanner T, Denayer S, Callewaert L, Claessens F: The Hinge Region Regulates DNA Binding, Nuclear Translocation, and Transactivation of the Androgen Receptor. Cancer Research 2007, 67: 4514-4523.

[37] Lee DK, Chang C: Endocrine Mechanisms of Disease: Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication. The Journal of Clinical Endocrinology and Metabolism 2003, 88: 4043-4054.

[38] Sheflin L, Keegan B, Zhang W, Spaulding SW: Inhibiting Proteasomes in Human HepG2 and LNCaP Cells Increases Endogenous Androgen Receptor Levels. Biochemical and Biophysical Research Communications 2000, 276: 144-150.

[39] Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C: Prostate-specific Membrane Antigen Expression in Normal and Malignant Human Tissues. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 1997, 3: 81-85.

[40] Wright GL Jr, Haley C, Beckett ML, Schellhammer PF: Expression of Prostate-specific Membrane Antigen in Normal, Benign, and Malignant Prostate Tissues. Urologic Oncology 1995, 1: 18-28.

[41] Rahn KA, Slusher BS, Kaplin AI: Glutamate in CNS Neurodegeneration and Cognition and Its Regulation by GCPII Inhibition. Current Medicinal Chemistry 2012, 19: 1335-1345.

[42] Rahn KA, Watkins CC, Alt J, Rais R, Stathis M, Grishkan I, et al.: Inhibition of Glutamate Carboxypeptidase II (GCPII) Activity as a Treatment for Cognitive Impairment in Multiple Sclerosis. Proceedings of the National Academy of Sciences of the United States of America 2012, 109: 20101-20106.

[43] Davis MI, Bennett MJ, Thomas LM, Bjorkman PJ: Crystal Structure of Prostate-specific Membrane Antigen, A Tumor Marker and Peptidase. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 5981-5986.

[44] Schulke N, Varlamova OA, Donovan GP, Ma D, Gardner JP, Morrissey DM, et al.: The Homodimer of Prostate-specific Membrane Antigen is a Functional Target for Cancer Therapy. Proceedings of the National Academy of Sciences of the United States of America 2003, 100: 12590-12595.

[45] Rawlings ND, Barrett AJ: Structure of Membrane Glutamate Carboxypeptidase. Biochimica et Biophysica Acta 1997, 1339: 247-252.

[46] Bernstein LH, Gutstein S, Weiner S, Efron G: The Absorption and Malabsorption of Folic Acid and Its Polyglutamates. The American Journal of Medicine 1970, 48: 570-579.

[47] Zhao R, Diop-Bove N, Visentin M, Goldman ID: Mechanisms of Membrane Transport of Folates into Cells and Across Epithelia. Annual Review of Nutrition 2011, 31: 177-201.

[48] Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al.: Folic Acid and Risk of Prostate Cancer: Results from a Randomized Clinical Trial. Journal of the National Cancer Institute 2009, 101: 432-435.

[49] Sanderson SM, Gao X, Dai Z, Locasale JW: Methionine Metabolism in Health and Cancer: A Nexus of Diet and Precision Medicine. Nature Reviews. Cancer 2019, 19: 625-637.

[50] Yao V, Bacich DJ: Prostate Specific Membrane Antigen (PSMA) Expression Gives Prostate Cancer Cells a Growth Advantage in a Physiologically Relevant Folate Environment In Vitro. The Prostate 2006, 66: 867-875.

[51] Corbin JM, Ruiz-Echevarría MJ: One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling. International Journal of Molecular Sciences 2016, 17: 1208.

[52] Zadra G, Ribeiro CF, Chetta P, Ho Y, Cacciatore S, Gao X, et al.: Inhibition of De Novo Lipogenesis Targets Androgen Receptor Signaling in Castration-resistant Prostate Cancer. Proceedings of the National Academy of Sciences of the United States of America 2019, 116: 631-640.

[53] Bakht MK, Beltran H: Biological Determinants of PSMA Expression, Regulation and Heterogeneity in Prostate Cancer. Nature Reviews Urology 2024, 22: 26-45.

[54] Neale JH, Bzdega T, Wroblewska B: N-Acetylaspartylglutamate: The Most Abundant Peptide Neurotransmitter in the Mammalian Central Nervous System. Journal of Neurochemistry 2000, 75: 443-452.

[55] Morland C, Nordengen K: N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease. International Journal of Molecular Sciences 2022, 23: 1268.

[56] Kaittanis C, Andreou C, Hieronymus H, Mao N, Foss CA, Eiber M, et al.: Prostate-specific Membrane Antigen Cleavage of Vitamin B9 Stimulates Oncogenic Signaling Through Metabotropic Glutamate Receptors. The Journal of Experimental Medicine 2018, 215: 159-175.

[57] Palamiuc L, Emerling BM: PSMA Brings New Flavors to PI3K Signaling: A Role for Glutamate in Prostate Cancer. The Journal of Experimental Medicine 2018, 215: 17-19.

[58] Bakht MK, Hayward JJ, Shahbazi-Raz F, Skubal M, Tamura R, Stringer KF, et al.: Identification of Alternative Protein Targets of Glutamate-ureido-lysine Associated with PSMA Tracer Uptake in Prostate Cancer Cells. Proceedings of the National Academy of Sciences of the United States of America 2022, 119: e2025710119. https://doi.org/10.1073/pnas.2025710119.

[59] Pellegrino S, Fonti R: A Look into the Future: The Role of PSMA Beyond Prostate Cancer. European Journal of Nuclear Medicine and Molecular Imaging 2023, 51: 278-280.

[60] Lee MS, Asomaning K, Su L, Wain JC, Mark EJ, Christiani DC: MTHFR Polymorphisms, Folate Intake and Carcinogen DNA Adducts in the Lung. International Journal of Cancer 2012, 131: 1203-1209.

[61] Yao V, Berkman CE, Choi JK, O’Keefe DS, Bacich DJ: Expression of Prostate-specific Membrane Antigen (PSMA), Increases Cell Folate Uptake and Proliferation and Suggests a Novel Role for PSMA in the Uptake of the Non-polyglutamated Folate, Folic Acid. The Prostate 2010, 70: 305-316.

[62] Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al.: Therapeutic Targeting of BET Bromodomain Proteins in Castration-resistant Prostate Cancer. Nature 2014, 510: 278-282.

[63] Nagarajan S, Hossan T, Alawi M, Najafova Z, Indenbirken D, Bedi U, et al.: Bromodomain Protein BRD4 is Required for Estrogen Receptor-dependent Enhancer Activation and Gene Transcription. Cell Reports 2014, 8: 460-469.

[64] Shi J, Vakoc CR: The Mechanisms Behind the Therapeutic Activity of BET Bromodomain Inhibition. Molecular Cell 2014, 54: 728-736.

[65] Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al.: BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc. Cell 2011, 146: 904-917.

[66] Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame MC, et al.: Inhibition of BET Bromodomain Proteins as a Therapeutic Approach in Prostate Cancer. Oncotarget 2013, 4: 2419-2429.

[67] Urbanucci A, Barfeld SJ, Kytola V, Itkonen HM, Coleman IM, Vodak D, et al.: Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Reports 2017, 19: 2045-2059.

[68] Romero Otero J, Garcia Gomez B, Campos Juanatey F, Touijer KA: Prostate Cancer Biomarkers: An Update. Urologic Oncology 2014, 32: 252-260.

[69] Lilja H: Testing New PSA Subforms to Enhance the Accuracy of Predicting Cancer Risk and Disease Outcome in Prostate Cancer. Clinical Chemistry 2008, 54: 1248-1249.

[70] Lilja H, Ulmert D, Vickers AJ: Prostate-specific Antigen and Prostate Cancer: Prediction, Detection and Monitoring. Nature Reviews. Cancer 2008, 8: 268-278.

[71] Cary KC, Cooperberg MR: Biomarkers in Prostate Cancer Surveillance and Screening: Past, Present, and Future. Therapeutic Advances in Urology 2013, 5: 318-329.

[72] Farha MW, Salami SS: Biomarkers for Prostate Cancer Detection and Risk Stratification. Therapeutic Advances in Urology 2022, 14:17562872221103988.

[73] Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL, et al.: A Prospective, Multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: Improving Prostate Cancer Detection and Correlating with Cancer Aggressiveness. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 2010, 19: 1193-1200.

[74] Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, et al.: DD3: A New Prostate-specific Gene, Highly Overexpressed in Prostate Cancer. Cancer Research 1999, 59: 5975-5979.

[75] de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, et al.: DD3(PCA3), A Very Sensitive and Specific Marker to Detect Prostate Tumors. Cancer Research 2002, 62: 2695-2698.

[76] Squire JA, Park PC, Yoshimoto M, Alami J, Williams JL, Evans A, et al.: Prostate Cancer as a Model System for Genetic Diversity in Tumors. Advances in Cancer Research 2011, 112: 183-216.

[77] Auprich M, Bjartell A, Chun FK, de la Taille A, Freedland SJ, Haese A, et al.: Contemporary Role of Prostate Cancer Antigen 3 in the Management of Prostate Cancer. European Urology 2011, 60: 1045-1054.

[78] Schoenborn JR, Nelson P, Fang M: Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2013, 19: 4058-4066.

[79] Crawford ED, Rove KO, Trabulsi EJ, Qian J, Drewnowska KP, Kaminetsky JC, et al.: Diagnostic Performance of PCA3 to Detect Prostate Cancer in Men with Increased Prostate Specific Antigen: A Prospective Study of 1,962 Cases. The Journal of Urology 2012, 188: 1726-1731.

[80] Vlaeminck-Guillem V, Ruffion A, Andre J, Devonec M, Paparel P: Urinary Prostate Cancer 3 Test: Toward the Age of Reason? Urology 2010, 75: 447-453.

[81] Kupelian PA, Buchsbaum JC, Elshaikh M, Reddy CA, Zippe C, Klein EA: Factors Affecting Recurrence Rates after Prostatectomy or Radiotherapy in Localized Prostate Carcinoma Patients with Biopsy Gleason Score 8 or Above. Cancer 2002, 95: 2302-2307.

[82] Sekhoacha M, Riet K, Motloung P, Gumenku L, Adegoke A, Mashele S: Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules 2022, 27: 5730.

[83] Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, et al.: Radiotherapy to the Primary Tumour for Newly Diagnosed, Metastatic Prostate Cancer (STAMPEDE): A Randomised Controlled Phase 3 Trial. Lancet 2018, 392: 2353-2366.

[84] Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al.: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. The New England Journal of Medicine 2015, 373: 737-746.

[85] Grewal K, Grewal K, Tabbara IA: PARP Inhibitors in Prostate Cancer. Anticancer Research 2021, 41: 551-556.

[86] Urbanucci A, Mills IG: Bromodomain-containing Proteins in Prostate Cancer. Molecular and Cellular Endocrinology 2018, 462: 31-40.

[87] Jones K, Zhang Y, Kong Y, Farah E, Wang R, Li C, et al.: Epigenetics in Prostate Cancer Treatment. Journal of Translational Genetics and Genomics 2021, 5: 341-356.

[88] Yan Y, Ma J, Wang D, Lin D, Pang X, Wang S, et al.: The Novel BET-CBP/p300 Dual Inhibitor NEO2734 is Active in SPOP Mutant and Wild-type Prostate Cancer. MBO Molecular Medicine 2019, 11: e10659.

[89] He Y, Wei T, Ye Z, Orme JJ, Lin D, Sheng H, et al.: A Noncanonical AR Addiction Drives Enzalutamide Resistance in Prostate Cancer. Nature Communications 2021, 12: 1521.

[90] Sun R, Yan B, Li H, Ding D, Wang L, Pang J, et al.: Androgen Receptor Variants Confer Castration Resistance in Prostate Cancer by Counteracting Antiandrogen-Induced Ferroptosis. Cancer Research 2023, 83: 3192-3204.

[91] Paller CJ, Piana D, Eshleman JR, Riel S, Denmeade SR, Isaacsson Velho P, et al.: A Pilot Study of Prostate-specific Membrane Antigen (PSMA) Dynamics in Men Undergoing Treatment for Advanced Prostate Cancer. The Prostate 2019, 79: 1597-1603.

[92] Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al.: Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. The New England Journal Medicine 2021, 385: 1091-1103.

[93] Pathmanandavel S, Crumbaker M, Yam AO, Nguyen A, Rofe C, Hovey E, et al.: ¹⁷⁷Lu-PSMA-617 and Idronoxil in Men with End-Stage Metastatic Castration-Resistant Prostate Cancer (LuPIN): Patient Outcomes and Predictors of Treatment Response in a Phase I/II Trial . Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine 2022, 63: 560-566.

[94] Aggarwal R, Starzinski S, de Kouchkovsky I, Koshkin V, Bose R, Chou J, et al.: Single-dose¹⁷⁷Lu-PSMA-617 Followed by Maintenance Pembrolizumab in Patients with Metastatic Castration-resistant Prostate Cancer: An Open-label, Dose-expansion, Phase 1 Trial . The Lancet. Oncology 2023, 24: 1266-1276.

[95] Ramnaraign B, Sartor O: PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials. The Oncologist 2023, 28: 392-401.

[96] Buchbinder EI, Desai A: CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. American Journal of Clinical Oncology 2016, 39: 98-106.

[97] Boudadi K, Suzman DL, Anagnostou V, Fu W, Luber B, Wang H, et al.: Ipilimumab Plus Nivolumab and DNA-repair Defects in AR-V7-expressing Metastatic Prostate Cancer. Oncotarget 2018, 9: 28561-28571.

[98] Shenderov E, Boudadi K, Fu W, Wang H, Sullivan R, Jordan A, et al.: Nivolumab Plus Ipilimumab, With or Without Enzalutamide, in AR-V7-expressing Metastatic Castration-Resistant Prostate Cancer: A Phase-2 Nonrandomized Clinical Trial. The Prostate 2021, 81: 326-338.

[99] Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis G, Galsky MD, et al.: Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. Cancer Cell 2020, 38: 489-499.e3.

[100] Kyriakopoulos CE, Eickhoff JC, Ferrari AC, Schweizer MT, Wargowski E, Olson BM, et al.: Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand-binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 2020, 26: 5162-5171.

[101] Antonarakis ES: Current Understanding of Resistance to Abiraterone and Enzalutamide in Advanced Prostate Cancer. Clinical Advances in Hematology & Oncology 2016, 14: 316-319.

[102] La J, Wang L, Corrigan JK, Lang D, Lee MH, Do NV, et al.: Abiraterone or Enzalutamide for Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Network Open 2024, 7: e2428444.

[103] Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al.: Enzalutamide in Metastatic Prostate Cancer Before Chemotherapy. The New England Journal of Medicine 2014, 371: 424-433.

[104] Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al.: Abiraterone Acetate Plus Prednisone Versus Placebo Plus Prednisone in Chemotherapy-naive Men with Metastatic Castration-resistant Prostate Cancer (COU-AA-302): Final Overall Survival Analysis of a Randomised, Double-blind, Placebo-controlled Phase 3 Study. The Lancet. Oncology 2015, 16: 152-160.

[105] Quinn DI, Sandler HM, Horvath LG, Goldkorn A, Eastham JA: The Evolution of Chemotherapy for the Treatment of Prostate Cancer. Annals of Oncology: Official Journal of the European Society for Medical Oncology 2017, 28: 2658-2669.

[106] Doyle-Lindrud S: Managing Side Effects of the Novel Taxane Cabazitaxel in Castrate-resistant Prostate Cancer. Clinical Journal of Oncology Nursing 2012, 16: 286-291.

[107] Yedla P, Babalghith AO, Andra VV, Syed R: PROTACs in the Management of Prostate Cancer. Molecules 2023, 28: 3698.

[108] Cooper G, Adams K: The Cell: A Molecular Approach . Oxford University Press; 2022.

[109] Ahn G, Banik SM, Miller CL, Riley NM, Cochran JR, Bertozzi CR: LYTACs That Engage the Asialoglycoprotein Receptor for Targeted Protein Degradation. Nature Chemical Biology 2021, 17: 937-946.

[110] Banik SM, Pedram K, Wisnovsky S, Ahn G, Riley NM, Bertozzi CR: Lysosome-targeting Chimaeras for Degradation of Extracellular Proteins. Nature 2020, 584: 291-297.

[111] Marei H, Tsai WK, Kee YS, Ruiz K, He J, Cox C, et al.: Antibody Targeting of E3 Ubiquitin Ligases for Receptor Degradation. Nature 2022, 610: 182-189.

[112] Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano JC, Cotton AD, et al.: Modular Cytokine Receptor-targeting Chimeras for Targeted Degradation of Cell Surface and Extracellular Proteins. Nature Biotechnology 2023, 41: 273-281.

[113] Zhang D, Duque-Jimenez J, Facchinetti F, Brixi G, Rhee K, Feng WW, et al.: Transferrin Receptor Targeting Chimeras for Membrane Protein Degradation. Nature 2024. doi: 10.1038/s41586-024-07947-3

[114] Hershko A, Ciechanover A: The Ubiquitin System. Annual Review of Biochemistry 1998, 67: 425-479.

[115] Komander D, Rape M: The Ubiquitin Code. Annual Review of Biochemistry 2012, 81: 203-229.

[116] Vogel G: Nobel Prizes. Gold Medal from Cellular Trash. Science 2004, 306: 400-401.

[117] Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, et al.: TAB2 and TAB3 Activate the NF-kappaB Pathway Through Binding to Polyubiquitin Chains. Molecular Cell 2004, 15: 535-548.

[118] Dang F, Nie L, Wei W: Ubiquitin Signaling in Cell Cycle Control and Tumorigenesis. Cell Death & Differentiation 2021, 28: 427-438.

[119] Mevissen TET, Komander D: Mechanisms of Deubiquitinase Specificity and Regulation. Annual Review of Biochemistry 2017, 86: 159-192.

[120] Guharoy M, Bhowmick P, Sallam M, Tompa P: Tripartite Degrons Confer Diversity and Specificity on Regulated Protein Degradation in the Ubiquitin-proteasome System. Nature Communication 2016, 7: 10239.

[121] Liu J, Tokheim C, Lee JD, Gan W, North BJ, Liu XS, et al.: Genetic Fusions Favor Tumorigenesis Through Degron Loss in Oncogenes. Nature Communication 2021, 12: 6704.

[122] Liu J, Ma J, Liu Y, Xia J, Li Y, Wang ZP, et al.: PROTACs: A Novel Strategy for Cancer Therapy. Seminars in Cancer Biology 2020, 67: 171-179.

[123] Takahashi D, Arimoto H: Targeting Selective Autophagy by AUTAC Degraders. Autophagy 2020, 16: 765-766.

[124] Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A, et al.: AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Molecular Cell 2019, 76: 797-810e10.

[125] Li Z, Wang C, Wang Z, Zhu C, Li J, Sha T, et al.: Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 2019, 575: 203-209.

[126] Li Z, Zhu C, Ding Y, Fei Y, Lu B: ATTEC: A Potential New Approach to Target Proteinopathies. Autophagy 2020, 16: 185-187.

[127] 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 2001, 98: 8554-8559.

[128] Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, et al.: Catalytic In Vivo Protein Knockdown by Small-molecule PROTACs. Nature Chemical Biology 2015, 11: 611-617.

[129] 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 2008, 18: 5904-5908.

[130] Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, et al.: DRUG DEVELOPMENT. Phthalimide Conjugation as a Strategy for In Vivo Target Protein Degradation. Science 2015, 348: 1376-1381.

[131] Sekine K, Takubo K, Kikuchi R, Nishimoto M, Kitagawa M, Abe F, et al.: Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation. The Journal of Biological Chemistry 2008, 283: 8961-8968.

[132] Lee J, Lee Y, Jung YM, Park JH, Yoo HS, Park J: Discovery of E3 Ligase Ligands for Target Protein Degradation. Molecules 2022, 27: 6515.

[133] Bricelj A, Steinebach C, Kuchta R, Gütschow M, Sosi I: E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Frontiers in Chemistry 2021, 9: 707317.

[134] Weng G, Shen C, Cao D, Gao J, Dong X, He Q, et al.: PROTAC-DB: An Online Database of PROTACs. Nucleic Acids Research 2021, 49: D1381-D1387.

[135] He S, Dong G, Cheng J, Wu Y, Sheng C: Strategies for Designing Proteolysis Targeting Chimaeras (PROTACs). Medicinal Research Reviews 2022, 42: 1280-1342.

[136] Troup RI, Fallan C, Baud MGJ: Current Strategies for the Design of PROTAC Linkers: A Critical Review. Exploration of Targeted Anti-tumor Therapy 2020, 1: 273-312.

[137] Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, Yang CY, 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. Journal of Medicinal Chemistry 2019, 62: 941-964.

[138] Morgenthaler M, Schweizer E, Hoffmann-Roder A, Benini F, Martin RE, Jaeschke G, et al.: Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities. ChemMedChem 2007, 2: 1100-1115.

[139] Wiberg KB: Substituent Effects on the Acidity of Weak Acids. 1. Bicyclo[2.2.2]octane-1-carboxylic Acids and bicyclo[1.1.1]pentane-1-carboxylic Acids. Journal of Organic Chemistry 2002, 67: 1613-1617.

[140] Davis C, Spaller BL, Matouschek A: Mechanisms of Substrate Recognition by the 26S Proteasome. Current Opinion in Structural Biology 2021, 67: 161-169.

[141] Eyre TA, Riches JC: The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives. Cancers (Basel) 2023, 15: 2596.

[142] Ackerman L, Acloque G, Bacchelli S, Schwartz H, Feinstein BJ, La Stella P, et al.: IRAK4 Degrader in Hidradenitis Suppurativa and Atopic Dermatitis: A Phase 1 Trial. Nature Medicine 2023, 29: 3127-3136.

[143] Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, et al.: Bruton Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer. Blood 2019, 133: 952-961.

[144] Zarrin AA, Bao K, Lupardus P, Vucic D: Kinase Inhibition in Autoimmunity and Inflammation. Nature Reviews. Drug Discovery 2021, 20: 39-63.

[145] Schiemer J, Horst R, Meng Y, Montgomery JI, Xu Y, Feng X, et al.: Snapshots and Ensembles of BTK and cIAP1 Protein Degrader Ternary Complexes. Natue Chemical Biology 2021, 17: 152-160.

[146] Zorba A, Nguyen C, Xu Y, Starr J, Borzilleri K, Smith J, et al.: Delineating the Role of Cooperativity in the Design of Potent PROTACs for BTK. Proceedings of the National Academy of Sciences of the United States of America 2018, 115: E7285-E7292.

[147] Tinworth CP, Lithgow H, Dittus L, Bassi ZI, Hughes SE, Muelbaier M, et al.: PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding. ACS Chemical Biology 2019, 14: 342-347.

[148] Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, et al.: Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation. Biochemistry 2018, 57: 3564-3575.

[149] Sun Y, Zhao X, Ding N, Gao H, Wu Y, Yang Y, et al.: PROTAC-induced BTK Degradation as a Novel Therapy for Mutated BTK C481S Induced Ibrutinib-resistant B-cell Malignancies. Cell Research 2018, 28: 779-781.

[150] Goedert M: Tau Protein and Neurodegeneration. Seminars in Cell & Developmental Biology 2004, 15: 45-49.

[151] Chang CW, Shao E, Mucke L: Tau: Enabler of Diverse Brain Disorders and Target of Rapidly Evolving Therapeutic Strategies. Science 2021, 371: eabb8255.

[152] DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, et al.: Tau Reduction Prevents Neuronal Loss and Reverses Pathological Tau Deposition and Seeding in Mice with Tauopathy. Science Translational Medicine 2017, 9: eaag0481.

[153] Wegmann S, DeVos SL, Zeitler B, Marlen K, Bennett RE, Perez-Rando M, et al.: Persistent Repression of Tau in the Brain Using Engineered Zinc Finger Protein Transcription Factors. Science Advances 2021, 7: eabe1611.

[154] Lu M, Liu T, Jiao Q, Ji J, Tao M, Liu Y, et al.: Discovery of a Keap1-dependent Peptide PROTAC to Knockdown Tau by Ubiquitination-proteasome Degradation Pathway. European Journal of Medicinal Chemistry 2018, 146: 251-259.

[155] Wang W, Zhou Q, Jiang T, Li S, Ye J, Zheng J, et al.: A Novel Small-molecule PROTAC Selectively Promotes Tau Clearance to Improve Cognitive Functions in Alzheimer-like Models. Theranostics 2021, 11: 5279-5295.

[156] Chien DT, Szardenings AK, Bahri S, Walsh JC, Mu F, Xia C, et al.: Early Clinical PET Imaging Results with the Novel PHF-tau Radioligand [F18]-T808. Journal of Alzheimer’s Disease 2014, 38: 171-184.

[157] Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, et al.: Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-derived Neuronal Cell Models. Elife 2019, 8: e45457.

[158] Kotzbauer PT, Trojanowsk JQ, Lee VM: Lewy Body Pathology in Alzheimer’s Disease. Journal of Molecular Neuroscience 2001, 17: 225-232.

[159] Qu J, Ren X, Xue F, He Y, Zhang R, Zheng Y, et al.: Specific Knockdown of α-Synuclein by Peptide-Directed Proteasome Degradation Rescued Its Associated Neurotoxicity. Cell Chemical Biology 2020, 27: 763.

[160] A Novel Gene Containing a Trinucleotide Repeat that is Expanded and Unstable on Huntington’s Disease Chromosomes. The Huntington’s Disease Collaborative Research Group . Cell 1993, 72: 971-983.

[161] Sap KA, Reits EA: Strategies to Investigate Ubiquitination in Huntington’s Disease. Frontiers in Chemistry 2020, 8: 485.

[162] Tomoshige S, Nomura S, Ohgane K, Hashimoto Y, Ishikawa M: Discovery of Small Molecules that Induce the Degradation of Huntingtin. Angewandte Chemie (International ed. in English) 2017, 56: 11530-11533.

[163] Li W, Deng X, Chen J: RNA-binding Proteins in Regulating mRNA Stability and Translation: Roles and Mechanisms in Cancer. Seminars in Cancer Biology 2022, 86: 664-677.

[164] Kelaini S, Chan C, Cornelius VA, Margariti A: RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease. Biology (Basel) 2021, 10: 366.

[165] Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM: A Census of Human Transcription Factors: Function, Expression and Evolution. Nature Reviews. Genetics 2009, 10: 252-263.

[166] Hagenbuchner J, Ausserlechner MJ: Targeting Transcription Factors by Small Compounds--Current Strategies and Future Implications. Biochemical Pharmacology 2016, 107: 1-13.

[167] Henley MJ, Koehler AN: Advances in Targeting ‘Undruggable’ Transcription Factors with Small Molecules. Nature Reviews. Drug Discovery 2021, 20: 669-688.

[168] Samarasinghe KTG, Jaime-Figueroa S, Burgess M, Nalawansha DA, Dai K, Hu Z, et al.: Targeted Degradation of Transcription Factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chemical Biology 2021, 28: 648-661.e5.

[169] Liu J, Chen H, Kaniskan HU, Xie L, Chen X, Jin J, et al.: TF-PROTACs Enable Targeted Degradation of Transcription Factors. Journal of the American Chemical Society 2021, 143: 8902-8910.

[170] Shao J, Yan Y, Ding D, Wang D, He Y, Pan Y, et al.: Destruction of DNA-Binding Proteins by Programmable Oligonucleotide PROTAC (O’PROTAC): Effective Targeting of LEF1 and ERG. Advanced Science (Weinheim, Baden-Wurttemberg, Germany) 2021, 8: e2102555.

[171] Patil KM, Chin D, Seah HL, Shi Q, Lim KW, Phan AT: G4-PROTAC: Targeted Degradation of a G-quadruplex Binding Protein. Chemical Communications 2021, 57: 12816-12819.

[172] Wang Z, Liu J, Chen H, Qiu X, Xie L, Kaniskan HU, et al.: Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins. Journal of the American Chemical Society 2023, 145: 10872-10879.

[173] Li X, Zhang Z, Gao F, Ma Y, Wei D, Lu Z, et al.: c-Myc-Targeting PROTAC Based on a TNA-DNA Bivalent Binder for Combination Therapy of Triple-Negative Breast Cancer. Journal of the American Chemical Society 2023, 145: 9334-9342.

[174] Wang Z, Liu J, Qiu X, Zhang D, Inuzuka H, Chen L, et al.: Methylated Nucleotide-Based Proteolysis-Targeting Chimera Enables Targeted Degradation of Methyl-CpG-Binding Protein 2. Journal of the American Chemical Society 2023, 145: 21871-21878.

[175] Wang Z, Zhang D, Qiu X, Inuzuka H, Xiong Y, Liu J, et al.: Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1. Journal of the American Chemical Society 2024, 146: 7584-7593.

[176] Xue G, Wang K, Zhou D, Zhong H, Pan Z: Light-Induced Protein Degradation with Photocaged PROTACs. Journal of the American Chemical Society 2019, 141: 18370-18374.

[177] Liu J, Chen H, Ma L, He Z, Wang D, Liu Y, et al.: Light-induced Control of Protein Destruction by Opto-PROTAC. Science Advances 2020, 6: eaay5154.

[178] Li Z, Ma S, Yang X, Zhang L, Liang D, Dong G, et al.: Development of Photocontrolled BRD4 PROTACs for Tongue Squamous Cell Carcinoma (TSCC). Europena Journal of Medicinal Chemistry 2021, 222: 113608.

[179] Naro Y, Darrah K, Deiters A: Optical Control of Small Molecule-Induced Protein Degradation. Journal of the American Chemical Society 2020, 142: 2193-2197.

[180] Kounde CS, Shchepinova MM, Saunders CN, Muelbaier M, Rackham MD, Harling JD, et al.: A Caged E3 Ligase Ligand for PROTAC-mediated Protein Degradation with Light. Chemical Communications (Cambridge, England) 2020, 56: 5532-5535.

[181] Pfaff P, Samarasinghe KTG, Crews CM, Carreira EM: Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs. ACS Central Science 2019, 5: 1682-1690.

[182] Liu J, Chen H, Liu Y, Shen Y, Meng F, Kaniskan HU, et al.: Cancer Selective Target Degradation by Folate-Caged PROTACs. Journal of the American Chemical Society 2021, 143: 7380-7387.

[183] Chen H, Liu J, Kaniskan HU, Wei W, Jin J: Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras. Journal of Medicinal Chemistry 2021, 64: 12273-12285.

[184] Cheng W, Li S, Wen X, Han S, Wang S, Wei H, et al.: Development of Hypoxia-activated PROTAC Exerting a More Potent Effect in Tumor Hypoxia than in Normoxia. Chemical Communications 2021, 57: 12852-12855.

[185] Shi S, Du Y, Zou Y, Niu J, Cai Z, Wang X, et al.: Rational Design for Nitroreductase (NTR)-Responsive Proteolysis Targeting Chimeras (PROTACs) Selectively Targeting Tumor Tissues. Journal of Medicinal Chemistry 2022, 65: 5057-5071.

[186] Yang C, Yang Y, Li Y, Ni Q, Li J: Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors. Journal of the American Chemical Society 2023, 145: 385-391.

[187] An K, Deng X, Chi H, Zhang Y, Li Y, Cheng M, et al.: Stimuli-Responsive PROTACs for Controlled Protein Degradation. Angewandte Chemie (International ed. in English) 2023, 62: e202306824.

[188] Gockel LM, Pfeifer V, Baltes F, Bachmaier RD, Wagner KG, Bendas G, et al.: Design, Synthesis, and Characterization of PROTACs Targeting the Androgen Receptor in Prostate and Lung Cancer Models. Archiv der Pharmazie (Weinheim) 2022, 355: e2100467.

[189] Takwale AD, Jo SH, Jeon YU, Kim HS, Shin CH, Lee HK, et al.: Design and Characterization of Cereblon-mediated Androgen Receptor Proteolysis-targeting Chimeras. European Journal of Medicinal Chemistry 2020, 208: 112769.

[190] Liang JJ, Xie H, Yang RH, Wang N, Zheng ZJ, Zhou C, et al.: Designed, Synthesized and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) as AR Degraders for Prostate Cancer Treatment. Bioorganic & Medicinal Chemistry 2021, 45: 116331.

[191] Kim GY, Song CW, Yang YS, Lee NR, Yoo HS, Son SH, et al.: Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog-Thalidomide PROTACs. Molecules 2021, 26: 2525.

[192] Han X, Zhao L, Xiang W, Qin C, Miao B, McEachern D, et al.: Strategies Toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer. Journal of Medicinal Chemistry 2021, 64: 12831-12854.

[193] Xiang W, Zhao L, Han X, Qin C, Miao B, McEachern D, et al.: Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer. Journal of Medicinal Chemistry 2021, 64: 13487-13509.

[194] Han X, Zhao L, Xiang W, Qin C, Miao B, Xu T, et al.: Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. Journal of Medicinal Chemistry 2019, 62: 11218-11231.

[195] Chen L, Han L, Mao S, Xu P, Xu X, Zhao R, et al.: Discovery of A031 as Effective Proteolysis Targeting Chimera (PROTAC) Androgen Receptor (AR) Degrader for the Treatment of Prostate Cancer. European Journal of Medicinal Chemistry 2021, 216: 113307.

[196] Munoz E, Chen G, Hossain A, Wu S, Oceguera Nava E, Hang J, et al.: Synthesis and Biological Evaluation of Niclosamide PROTACs. Bioorganic & Medicinal Chemistry Letters 2022, 72: 128870.

[197] Lee GT, Nagaya N, Desantis J, Madura K, Sabaawy HE, Kim WJ, et al.: Effects of MTX-23, A Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy. Molecular Cancer Therapeutics 2021, 20: 490-499.

[198] Lotem J, Sachs L: Genetic Dissection of the Control of Normal Differentiation in Myeloid Leukemic Cells. Proceedings of the National Academy of Sciences of the United States of America 1977, 74: 5554-5558.

[199] Kregel S, Wang C, Han X, Xiao L, Fernandez-Salas E, Bawa P, et al.: Androgen Receptor Degraders Overcome Common Resistance Mechanisms Developed During Prostate Cancer Treatment. Neoplasia 2020, 22: 111-119.

[200] Zhang B, Liu C, Yang Z, Zhang S, Hu X, Li B, et al.: Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer. Journal of Medicinal Chemistry 2023, 66: 11158-11186.

[201] Han X, Zhao L, Xiang W, Miao B, Qin C, Wang M, et al.: Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer. Journal of Medicinal Chemistry 2023, 66: 8822-8843.

[202] Xiang W, Zhao L, Han X, Xu T, Kregel S, Wang M, et al.: Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer. Journal of Medicinal Chemistry 2023, 66: 13280-13303.

[203] Ma L, Wang J, Zhang Y, Fang F, Ling J, Chu X, et al.: BRD4 PROTAC Degrader MZ1 Exerts Anticancer Effects in Acute Myeloid Leukemia by Targeting c-Myc and ANP32B Genes. Cancer Biology & Therapy 2022, 23: 1-15.

[204] Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, et al.: PROTAC-induced BET Protein Degradation as a Therapy for Castration-resistant Prostate Cancer. Proceedings of the National Academy of Sciences of the United States of America 2016, 113: 7124-7129.

[205] Slabicki M, Yoon H, Koeppel J, Nitsch L, Roy Burman SS, Di Genua C, et al.: Small-molecule-induced Polymerization Triggers Degradation of BCL6. Nature 2020, 588: 164-168.

[206] Cromm PM, Samarasinghe KTG, Hines J, Crews CM: Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation. Journal of the American Chemical Society 2018, 140: 17019-17026.

[207] Jiang B, Wang ES, Donovan KA, Liang Y, Fischer ES, Zhang T, et al.: Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6. Angewandte Chemie (International ed. in English) 2019, 58: 6321-6326.

[208] Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, et al.: Bromodomain and Extraterminal (BET) Proteins: Biological Functions, Diseases, and Targeted Therapy. Signal Transduction and Targeted Therapy 2023, 8: 420.

[209] Sherr CJ, Beach D, Shapiro GI: Targeting CDK4 and CDK6: From Discovery to Therapy. Cancer Discovery 2016, 6: 353-367.

[210] Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al.: In Vivo Amplification of the Androgen Receptor Gene and Progression of Human Prostate Cancer. Nature Genetics 1995, 9: 401-406.

[211] Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, et al.: Survey of Gene Amplifications During Prostate Cancer Progression by High-throughout Fluorescence In Situ Hybridization on Tissue Microarrays. Cancer Research 1999, 59: 803-806.

[212] Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T: Amplification and Overexpression of Androgen Receptor Gene in Hormone-refractory Prostate Cancer. Cancer Research 2001, 61: 3550-3555.

[213] Wadosky KM, Koochekpour S: Molecular Mechanisms Underlying Resistance to Androgen Deprivation Therapy in Prostate Cancer. Oncotarget 2016, 7: 64447-64470.

[214] Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al.: Molecular Determinants of Resistance to Antiandrogen Therapy. Nature Medicine 2004, 10: 33-39.

[215] van der Steen T, Tindall DJ, Huang H: Posttranslational modification of the androgen receptor in prostate cancer. International Journal of Molecular Sciences 2013, 14: 14833-14859.

[216] Azad AA, Zoubeidi A, Gleave ME, Chi KN: Targeting Heat Shock Proteins in Metastatic Castration-resistant Prostate Cancer. Nature Reviews Urology 2015, 12: 26-36.

[217] Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al.: Ligand-independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-refractory Prostate Cancer. Cancer Research 2009, 69: 16-22.

[218] Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ: Splicing of a Novel Androgen Receptor Exon Generates a Constitutively Active Androgen Receptor that Mediates Prostate Cancer Therapy Resistance. Cancer Research 2008, 68: 5469-5477.

[219] Nakazawa M, Antonarakis ES, Luo J: Androgen Receptor Splice Variants in the Era of Enzalutamide and Abiraterone. Hormones & Cancer 2014, 5: 265-273.

[220] Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al.: AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer. The New England Journal of Medicine 2014, 371: 1028-1038.

[221] Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al.: Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. The New England Journal of Medicine 2012, 367: 1187-1197.

[222] de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al.: Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England Journal of Medicine 2011, 364: 1995-2005.

[223] Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al.: Abiraterone in Metastatic Prostate Cancer Without Previous Chemotherapy. The New England Journal of Medicine 2013, 368: 138-148.