1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pharmacology and Toxicology
  4. Volume 65, 2025
  5. Article

Annual Review of Pharmacology and Toxicology

Volume 65, 2025

PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer

Abstract

Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.

Keyword(s): castration resistance, drug discovery, prostate cancer, PROTAC, proteolysis targeting chimera
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-030624-110238
2025-01-23
2025-04-20
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/65/1/annurev-pharmtox-030624-110238.html?itemId=/content/journals/10.1146/annurev-pharmtox-030624-110238&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, et al. 2015.. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). . Eur. Urol. 67::482–91
     [Crossref] [Google Scholar]
  2. 2.
    Rice MA, Malhotra SV, Stoyanova T. 2019.. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. . Front. Oncol. 9::801
     [Crossref] [Google Scholar]
  3. 3.
    Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, et al. 2018.. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. . J. Clin. Oncol. 36::2492–503
     [Crossref] [Google Scholar]
  4. 4.
    Abida W, Cyrta J, Heller G, Prandi D, Armenia J, et al. 2019.. Genomic correlates of clinical outcome in advanced prostate cancer. . PNAS 116::11428–36
     [Crossref] [Google Scholar]
  5. 5.
    Bekes M, Langley DR, Crews CM. 2022.. PROTAC targeted protein degraders: The past is prologue. . Nat. Rev. Drug Discov. 21::181–200
     [Crossref] [Google Scholar]
  6. 6.
    Yedla P, Babalghith AO, Andra VV, Syed R. 2023.. PROTACs in the management of prostate cancer. . Molecules 28::3698
     [Crossref] [Google Scholar]
  7. 7.
    Petrylak DP, Gao X, Vogelzang NJ, Garfield MH, Taylor I, et al. 2020.. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). . J. Clin. Oncol. 38::3500
     [Crossref] [Google Scholar]
  8. 8.
    Gao X, Burris HA III, Vuky J, Dreicer R, Sartor AO, et al. 2022.. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). . J. Clin. Oncol. 40::17
     [Crossref] [Google Scholar]
  9. 9.
    Petrylak DP, Stewart TF, Gao X, Berghorn E, Lu H, et al. 2023.. A phase 2 expansion study of ARV-766, a PROTAC androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC). . J. Clin. Oncol. 41::TPS290
     [Crossref] [Google Scholar]
  10. 10.
    Sakamoto KM, Kim KB, Verma R, Ransick A, Stein B, et al. 2003.. Development of PROTACs to target cancer-promoting proteins for ubiquitination and degradation. . Mol. Cell Proteom. 2::1350–58
     [Crossref] [Google Scholar]
  11. 11.
    Dai C, Heemers H, Sharifi N. 2017.. Androgen signaling in prostate cancer. . Cold Spring Harb. Perspect. Med. 7::a030452
     [Crossref] [Google Scholar]
  12. 12.
    Feng Q, He B. 2019.. Androgen receptor signaling in the development of castration-resistant prostate cancer. . Front. Oncol. 9::858
     [Crossref] [Google Scholar]
  13. 13.
    Watson PA, Arora VK, Sawyers CL. 2015.. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. . Nat. Rev. Cancer 15::701–11
     [Crossref] [Google Scholar]
  14. 14.
    Chandrasekar T, Yang JC, Gao AC, Evans CP. 2015.. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). . Transl. Androl. Urol. 4::365–80
     [Google Scholar]
  15. 15.
    Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, et al. 2017.. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. . J. Clin. Oncol. 35::2149–56
     [Crossref] [Google Scholar]
  16. 16.
    Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, et al. 2019.. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. . J. Clin. Investig. 129::192–208
     [Crossref] [Google Scholar]
  17. 17.
    Rajaram P, Rivera A, Muthima K, Olveda N, Muchalski H, Chen Q-H. 2020.. Second-generation androgen receptor antagonists as hormonal therapeutics for three forms of prostate cancer. . Molecules 25::2448
     [Crossref] [Google Scholar]
  18. 18.
    Mohler ML, Sikdar A, Ponnusamy S, Hwang D-J, He Y, et al. 2021.. An overview of next-generation androgen receptor-targeted therapeutics in development for the treatment of prostate cancer. . Int. J. Mol. Sci. 22::2124
     [Crossref] [Google Scholar]
  19. 19.
    Chen Y, Zhou Q, Hankey W, Fang X, Yuan F. 2022.. Second generation androgen receptor antagonists and challenges in prostate cancer treatment. . Cell Death Dis. 13::632
     [Crossref] [Google Scholar]
  20. 20.
    Pinto F, Dibitetto F, Ragonese M, Bassi P. 2022.. Mechanisms of resistance to second-generation antiandrogen therapy for prostate cancer: actual knowledge and perspectives. . Med. Sci. 10::25
     [Google Scholar]
  21. 21.
    Borgmann H, Lallous N, Ozistanbullu D, Beraldi E, Paul N, et al. 2018.. Moving towards precision urologic oncology: targeting enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor using the novel inhibitor darolutamide (ODM-201). . Eur. Urol. 73::4–8
     [Crossref] [Google Scholar]
  22. 22.
    Liang A, Dowst H, Zarrin-Khameh N, Huang Q, Noor AB, et al. 2023.. Real-world effectiveness of darolutamide in metastatic castration-resistant prostate cancer: Experience from a safety-net hospital serving a racially and ethnically diverse patient population. . J. Clin. Oncol. 41::150
     [Crossref] [Google Scholar]
  23. 23.
    Zhao J, Ning S, Lou W, Yang JC, Armstrong CM, et al. 2020.. Cross-resistance among next-generation antiandrogen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer. . Mol. Cancer Ther. 19::1708–18
     [Crossref] [Google Scholar]
  24. 24.
    Flanagan JJ, Neklesa TK. 2019.. Targeting nuclear receptors with PROTAC degraders. . Mol. Cell Endocrinol. 493::110452
     [Crossref] [Google Scholar]
  25. 25.
    Schneekloth JS Jr., Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, et al. 2004.. Chemical genetic control of protein levels: selective in vivo targeted degradation. . J. Am. Chem. Soc. 126::3748–54
     [Crossref] [Google Scholar]
  26. 26.
    Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, et al. 2008.. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. . Oncogene 27::7201–11
     [Crossref] [Google Scholar]
  27. 27.
    Tang YQ, Han BM, Yao XQ, Hong Y, Wang Y, et al. 2009.. Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells. . Asian J. Androl. 11::119–26
     [Crossref] [Google Scholar]
  28. 28.
    Jin J, Wu Y, Chen J, Shen Y, Zhang L, et al. 2020.. The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination. . Theranostics 10::10141–53
     [Crossref] [Google Scholar]
  29. 29.
    Schneekloth AR, Pucheault M, Tae HS, Crews CM. 2008.. Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. . Bioorg. Med. Chem. Lett. 18::5904–8
     [Crossref] [Google Scholar]
  30. 30.
    Salami J, Alabi S, Willard RR, Vitale NJ, Wang J, et al. 2018.. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. . Commun. Biol. 1::100
     [Crossref] [Google Scholar]
  31. 31.
    Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, et al. 2019.. 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. 62::941–64
     [Crossref] [Google Scholar]
  32. 32.
    Han X, Zhao L, Xiang W, Qin C, Miao B, et al. 2019.. Discovery of highly potent and efficient PROTAC degraders of androgen receptor (AR) by employing weak binding affinity VHL E3 ligase ligands. . J. Med. Chem. 62::11218–31
     [Crossref] [Google Scholar]
  33. 33.
    Kregel S, Wang C, Han X, Xiao L, Fernandez-Salas E, et al. 2020.. Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment. . Neoplasia 22::111–19
     [Crossref] [Google Scholar]
  34. 34.
    Bricelj A, Steinebach C, Kuchta R, Gutschow M, Sosic I. 2021.. E3 ligase ligands in successful PROTACs: an overview of syntheses and linker attachment points. . Front. Chem. 9::707317
     [Crossref] [Google Scholar]
  35. 35.
    Takwale AD, Jo SH, Jeon YU, Kim HS, Shin CH, et al. 2020.. Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras. . Eur. J. Med. Chem. 208::112769
     [Crossref] [Google Scholar]
  36. 36.
    Kim G-Y, Song CW, Yang Y-S, Lee N-R, Yoo H-S, et al. 2021.. Chemical degradation of androgen receptor (AR) using bicalutamide analog–thalidomide PROTACs. . Molecules 26::2525
     [Crossref] [Google Scholar]
  37. 37.
    Liang JJ, Xie H, Yang RH, Wang N, Zheng ZJ, et al. 2021.. Designed, synthesized and biological evaluation of proteolysis targeting chimeras (PROTACs) as AR degraders for prostate cancer treatment. . Bioorg. Med. Chem. 45::116331
     [Crossref] [Google Scholar]
  38. 38.
    Han X, Zhao L, Xiang W, Qin C, Miao B, et al. 2021.. Strategies toward discovery of potent and orally bioavailable proteolysis targeting chimera degraders of androgen receptor for the treatment of prostate cancer. . J. Med. Chem. 64::12831–54
     [Crossref] [Google Scholar]
  39. 39.
    Xiang W, Zhao L, Han X, Qin C, Miao B, et al. 2021.. Discovery of ARD-2585 as an exceptionally potent and orally active PROTAC degrader of androgen receptor for the treatment of advanced prostate cancer. . J. Med. Chem. 64::13487–509
     [Crossref] [Google Scholar]
  40. 40.
    Han X, Zhao L, Xiang W, Miao B, Qin C, et al. 2023.. 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. . J. Med. Chem. 66::8822–43
     [Crossref] [Google Scholar]
  41. 41.
    Xiang W, Zhao L, Han X, Xu T, Kregel S, et al. 2023.. 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. . J. Med. Chem. 66::13280–303
     [Crossref] [Google Scholar]
  42. 42.
    Li H, Ban F, Dalal K, Leblanc E, Frewin K, et al. 2014.. Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor. . J. Med. Chem. 57::6458–67
     [Crossref] [Google Scholar]
  43. 43.
    Dalal K, Roshan-Moniri M, Sharma A, Li H, Ban F, et al. 2014.. Selectively targeting the DNA-binding domain of the androgen receptor as a prospective therapy for prostate cancer. . J. Biol. Chem. 289::26417–29
     [Crossref] [Google Scholar]
  44. 44.
    Dalal K, Che M, Que NS, Sharma A, Yang R, et al. 2017.. Bypassing drug resistance mechanisms of prostate cancer with small molecules that target androgen receptor–chromatin interactions. . Mol. Cancer Ther. 16::2281–91
     [Crossref] [Google Scholar]
  45. 45.
    Lee GT, Nagaya N, Desantis J, Madura K, Sabaawy HE, et al. 2021.. Effects of MTX-23, a novel PROTAC of androgen receptor splice variant-7 and androgen receptor, on CRPC resistant to second-line antiandrogen therapy. . Mol. Cancer Ther. 20::490–99
     [Crossref] [Google Scholar]
  46. 46.
    Ma B, Fan Y, Zhang D, Wei Y, Jian Y, et al. 2022.. De novo design of an androgen receptor DNA binding domain-targeted peptide PROTAC for prostate cancer therapy. . Adv. Sci. 9::e2201859
     [Crossref] [Google Scholar]
  47. 47.
    Monti A, Vitagliano L, Caporale A, Ruvo M, Doti N. 2023.. Targeting protein–protein interfaces with peptides: the contribution of chemical combinatorial peptide library approaches. . Int. J. Mol. Sci. 24::7842
     [Crossref] [Google Scholar]
  48. 48.
    Jiang X, Du B, Huang Y, Zheng J. 2018.. Ultrasmall noble metal nanoparticles: breakthroughs and biomedical implications. . Nano Today 21::106–25
     [Crossref] [Google Scholar]
  49. 49.
    Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, et al. 2010.. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. . Cancer Cell 17::535–46
     [Crossref] [Google Scholar]
  50. 50.
    Myung JK, Banuelos CA, Fernandez JG, Mawji NR, Wang J, et al. 2013.. An androgen receptor N-terminal domain antagonist for treating prostate cancer. . J. Clin. Investig. 123::2948–60
     [Crossref] [Google Scholar]
  51. 51.
    Yang YC, Banuelos CA, Mawji NR, Wang J, Kato M, et al. 2016.. Targeting androgen receptor activation function-1 with EPI to overcome resistance mechanisms in castration-resistant prostate cancer. . Clin. Cancer Res. 22::4466–77
     [Crossref] [Google Scholar]
  52. 52.
    Ponnusamy S, Coss CC, Thiyagarajan T, Watts K, Hwang D-J, et al. 2017.. Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer. . Cancer Res. 77::6282–98
     [Crossref] [Google Scholar]
  53. 53.
    Ponnusamy S, He Y, Hwang D-J, Thiyagarajan T, Houtman R, et al. 2019.. Orally bioavailable androgen receptor degrader, potential next-generation therapeutic for enzalutamide-resistant prostate cancer. . Clin. Cancer Res. 25::6764–80
     [Crossref] [Google Scholar]
  54. 54.
    He Y, Hwang D-J, Ponnusamy S, Thiyagarajan T, Mohler ML, et al. 2021.. Exploration and biological evaluation of basic heteromonocyclic propanamide derivatives as SARDs for the treatment of enzalutamide-resistant prostate cancer. . J. Med. Chem. 64::11045–62
     [Crossref] [Google Scholar]
  55. 55.
    Le Moigne R, Zhou H-J, Obst JK, Banuelos CA, Jian K, et al. 2019.. Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor. . J. Clin. Oncol. 37::257
     [Crossref] [Google Scholar]
  56. 56.
    Pachynski RK, Iannotti N, Laccetti AL, Carthon BC, Chi KN, et al. 2023.. Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer. . J. Clin. Oncol. 41::177
     [Crossref] [Google Scholar]
  57. 57.
    Sayyid R. 2024.. Phase 1 results and Phase 2 design - oral EPI-7386 (masofaniten) in combination with enzalutamide compared to enzalutamide alone in patients with mCRPC. Written during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA:, Jan. 25–27
    [Google Scholar]
  58. 58.
    Hong NH, Biannic B, Virsik P, Zhou H-J, Moigne RL. 2022.. Androgen receptor (AR) N-terminal domain degraders can degrade AR full length and AR splice variants in CRPC preclinical models. . Cancer Res. 82::429 ( Abstr. )
     [Crossref] [Google Scholar]
  59. 59.
    Zhang B, Liu C, Yang Z, Zhang S, Hu X, et al. 2023.. 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. . J. Med. Chem. 66::11158–86
     [Crossref] [Google Scholar]
  60. 60.
    Grimster NP. 2021.. Covalent PROTACs: the best of both worlds?. RSC Med. Chem. 12::1452–58
     [Crossref] [Google Scholar]
  61. 61.
    Hung C-L, Liu H-H, Fu C-W, Yeh H-H, Hu T-L, et al. 2023.. Targeting androgen receptor and the variants by an orally bioavailable proteolysis targeting chimeras compound in castration resistant prostate cancer. . EBioMedicine 90::104500
     [Crossref] [Google Scholar]
  62. 62.
    Hung C-L, Wang L-Y, Fu C-W, Hsu H-C, Kung H-J. 2023.. An orally bioavailable degrader targeting androgen receptor and the splice variant in castration resistant prostate cancer. . Cancer Res. 83::LB133 ( Abstr. )
     [Crossref] [Google Scholar]
  63. 63.
    Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, et al. 2013.. Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. . Bioorg. Med. Chem. Lett. 23::1945–48
     [Crossref] [Google Scholar]
  64. 64.
    Loddick SA, Ross SJ, Thomason AG, Robinson DM, Walker GE, et al. 2013.. AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. . Mol. Cancer Ther. 12::1715–27
     [Crossref] [Google Scholar]
  65. 65.
    Neklesa T, Snyder LB, Willard RR, Vitale N, Pizzano J, et al. 2019.. ARV-110: an oral androgen receptor PROTAC degrader for prostate cancer. . J. Clin. Oncol. 37::259
     [Crossref] [Google Scholar]
  66. 66.
    Snyder L, Lee SH, Neklesa TK, Chen X, Dong H, et al. 2023.. Discovery of ARV-766, an androgen receptor degrading PROTAC® for the treatment of men with metastatic castration resistant prostate cancer. . Cancer Res. 83::ND03 ( Abstr. )
     [Crossref] [Google Scholar]
  67. 67.
    Jernberg E, Bergh A, Wikström P. 2017.. Clinical relevance of androgen receptor alterations in prostate cancer. . Endocr. Connect. 6::R146–61
     [Crossref] [Google Scholar]
  68. 68.
    Antonarakis ES, Zhang N, Saha J, Nevalaita L, Shell SA, et al. 2023.. Real-world assessment of AR-LBD mutations in metastatic castration-resistant prostate cancer. . J. Clin. Oncol. 41::204
     [Crossref] [Google Scholar]
  69. 69.
    Rathkopf DE, Patel MR, Choudhury AD, Rasco DW, Lakhani NJ, et al. 2024.. First-in-human phase 1 study of CC-94676, a first-in-class androgen receptor (AR) ligand-directed degrader (LDD), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). . J. Clin. Oncol. 42::134
     [Crossref] [Google Scholar]
  70. 70.
    Klaassen Z. 2024.. Preliminary data from a dose-escalation phase 1 study with HP518, an AR PROTAC degrader: safety, tolerability, pharmacokinetics, and first assessment of anti-tumor activity in patients with mCRPC. Written during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA:, Jan. 25–27
    [Google Scholar]
  71. 71.
    Wang J, Qian M, Yan P, Li L, Zhang C, et al. 2023.. HSK38008: an oral AR-V7 degrader for metastatic castration-resistant prostate cancer. . Cancer Res. 83::LB262 ( Abstr. )
     [Crossref] [Google Scholar]
  72. 72.
    Njar VCO, Brodie AM. 2015.. Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer. . J. Med. Chem. 58::2077–87
     [Crossref] [Google Scholar]
  73. 73.
    Kwegyir-Afful AK, Ramalingam S, Purushottamachar P, Ramamurthy VP, Njar VCO. 2015.. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo. . Oncotarget 6::27440–60
     [Crossref] [Google Scholar]
  74. 74.
    Taplin M-E, Antonarakis ES, Ferrante KJ, Horgan K, Blumenstein BA, et al. 2017.. Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) versus enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC). . J. Clin. Oncol. 35::5005
     [Crossref] [Google Scholar]
  75. 75.
    Kwegyir-Afful AK, Ramalingam S, Ramamurthy VP, Purushottamachar P, Murigi FN, et al. 2019.. Galeterone and the next generation galeterone analogs, VNPP414 and VNPP433-3beta exert potent therapeutic effects in castration-/drug-resistant prostate cancer preclinical models in vitro and in vivo. . Cancers 11::1637
     [Crossref] [Google Scholar]
  76. 76.
    Thomas E, Thankan RS, Purushottamachar P, Weber DJ, Njar VCO. 2023.. Targeted degradation of androgen receptor by VNPP433-3β in castration-resistant prostate cancer cells implicates interaction with E3 ligase MDM2 resulting in ubiquitin-proteasomal degradation. . Cancers 15::1198
     [Crossref] [Google Scholar]
  77. 77.
    Lv S, Song Q, Chen G, Cheng E, Chen W, et al. 2021.. Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer. . J. Clin. Investig. 131::e141335
     [Crossref] [Google Scholar]
  78. 78.
    Yu EY, Yazji S, Katz Y, Coates E, Nordquist LT, et al. 2024.. A phase 1/2 study of ONCT-534, a dual-action androgen receptor inhibitor (DAARI), in patients with metastatic castration-resistant prostate cancer. . J. Clin. Oncol. 42::TPS241
     [Crossref] [Google Scholar]
  79. 79.
    Narayanan R. 2021.. Androgen receptor (AR) N-terminus-domain-binding small molecule degraders for the treatment of AR splice variant-positive castration-resistant prostate cancer. . Mol. Cancer Ther. 20::LBA016 ( Abstr. )
     [Crossref] [Google Scholar]
  80. 80.
    Thiyagarajan T, Ponnusamy S, Hwang D-J, He Y, Asemota S, et al. 2023.. Inhibiting androgen receptor splice variants with cysteine-selective irreversible covalent inhibitors to treat prostate cancer. . PNAS 120::e2211832120
     [Crossref] [Google Scholar]
  81. 81.
    Wu YL, Yang X, Ren Z, McDonnell DP, Norris JD, et al. 2005.. Structural basis for an unexpected mode of SERM-mediated ER antagonism. . Mol. Cell 18::413–24
     [Crossref] [Google Scholar]
  82. 82.
    Filippakopoulos P, Knapp S. 2014.. Targeting bromodomains: epigenetic readers of lysine acetylation. . Nat. Rev. Drug Discov. 13::337–56
     [Crossref] [Google Scholar]
  83. 83.
    Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, et al. 2013.. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. . Oncotarget 4::2419–29
     [Crossref] [Google Scholar]
  84. 84.
    Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, et al. 2014.. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. . Nature 510::278–82
     [Crossref] [Google Scholar]
  85. 85.
    Faivre EJ, Wilcox D, Lin X, Hessler P, Torrent M, et al. 2017.. Exploitation of castration-resistant prostate cancer transcription factor dependencies by the novel BET inhibitor ABBV-075. . Mol. Cancer Res. 15::35–44
     [Crossref] [Google Scholar]
  86. 86.
    Kim DH, Sun D, Storck WK, Welker Leng K, Jenkins C, et al. 2021.. BET bromodomain inhibition blocks an AR-repressed, E2F1-activated treatment-emergent neuroendocrine prostate cancer lineage plasticity program. . Clin. Cancer Res. 27::4923–36
     [Crossref] [Google Scholar]
  87. 87.
    To KKW, Xing E, Larue RC, Li P-K. 2023.. BET bromodomain inhibitors: novel design strategies and therapeutic applications. . Molecules 28::3043
     [Crossref] [Google Scholar]
  88. 88.
    Mandl A, Markowski MC, Carducci MA, Antonarakis ES. 2023.. Role of bromodomain and extraterminal (BET) proteins in prostate cancer. . Expert Opin. Investig. Drugs 32::213–28
     [Crossref] [Google Scholar]
  89. 89.
    Raina K, Lu J, Qian Y, Altieri M, Gordon D, et al. 2016.. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. . PNAS 113::7124–29
     [Crossref] [Google Scholar]
  90. 90.
    Li Z, Lim SL, Tao Y, Li X, Xie Y, et al. 2020.. PROTAC bromodomain inhibitor ARV-825 displays anti-tumor activity in neuroblastoma by repressing expression of MYCN or c-Myc. . Front. Oncol. 10::574525
     [Crossref] [Google Scholar]
  91. 91.
    Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, et al. 2016.. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. . Cancer Cell 29::536–47
     [Crossref] [Google Scholar]
  92. 92.
    Hu R, Wang WL, Yang YY, Hu XT, Wang QW, et al. 2022.. Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor. . Eur. J. Med. Chem. 227::113922
     [Crossref] [Google Scholar]
  93. 93.
    Dragovich PS, Pillow TH, Blake RA, Sadowsky JD, Adaligil E, et al. 2021.. Antibody-mediated delivery of chimeric BRD4 degraders. Part 1: exploration of antibody linker, payload loading, and payload molecular properties. . J. Med. Chem. 64::2534–75
     [Crossref] [Google Scholar]
  94. 94.
    Xue G, Wang K, Zhou D, Zhong H, Pan Z. 2019.. Light-induced protein degradation with photocaged PROTACs. . J. Am. Chem. Soc. 141::18370–74
     [Crossref] [Google Scholar]
  95. 95.
    Hu Z, Crews CM. 2022.. Recent developments in PROTAC-mediated protein degradation: from bench to clinic. . ChemBioChem 23::e202100270
     [Crossref] [Google Scholar]
  96. 96.
    Xu K, Wu ZJ, Groner AC, He HH, Cai C, et al. 2012.. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. . Science 338::1465–69
     [Crossref] [Google Scholar]
  97. 97.
    Wang J, Park K-S, Yu X, Gong W, Earp HS, et al. 2022.. A cryptic transactivation domain of EZH2 binds AR and AR's splice variant, promoting oncogene activation and tumorous transformation. . Nucleic Acids Res. 50::10929–46
     [Crossref] [Google Scholar]
  98. 98.
    Kim J, Lee Y, Lu X, Song B, Fong KW, et al. 2018.. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. . Cell Rep. 25::2808–20.e4
     [Crossref] [Google Scholar]
  99. 99.
    Davies A, Zoubeidi A, Selth LA. 2020.. The epigenetic and transcriptional landscape of neuroendocrine prostate cancer. . Endocr. Relat. Cancer 27::R35–50
     [Crossref] [Google Scholar]
  100. 100.
    Davies A, Nouruzi S, Ganguli D, Namekawa T, Thaper D, et al. 2021.. An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer. . Nat. Cell Biol. 23::1023–34
     [Crossref] [Google Scholar]
  101. 101.
    Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, et al. 2002.. The polycomb group protein EZH2 is involved in progression of prostate cancer. . Nature 419::624–29
     [Crossref] [Google Scholar]
  102. 102.
    Beltran H, Rickman DS, Park K, Chae SS, Sboner A, et al. 2011.. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. . Cancer Discov. 1::487–95
     [Crossref] [Google Scholar]
  103. 103.
    Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, et al. 2018.. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. . Nat. Commun. 9::4080
     [Crossref] [Google Scholar]
  104. 104.
    Liu Y, Yang Q. 2023.. The roles of EZH2 in cancer and its inhibitors. . Med. Oncol. 40::167
     [Crossref] [Google Scholar]
  105. 105.
    Guo Y, Cheng R, Wang Y, Gonzalez ME, Zhang H, et al. 2024.. Regulation of EZH2 protein stability: new mechanisms, roles in tumorigenesis, and roads to the clinic. . EBioMedicine 100::104972
     [Crossref] [Google Scholar]
  106. 106.
    Wang J, Yu X, Gong W, Liu X, Park K-S, et al. 2022.. EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis. . Nat. Cell Biol. 24::384–99
     [Crossref] [Google Scholar]
  107. 107.
    Wilson BG, Roberts CW. 2011.. SWI/SNF nucleosome remodellers and cancer. . Nat. Rev. Cancer 11::481–92
     [Crossref] [Google Scholar]
  108. 108.
    Wanior M, Kramer A, Knapp S, Joerger AC. 2021.. Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. . Oncogene 40::3637–54
     [Crossref] [Google Scholar]
  109. 109.
    Dreier MR, Walia J, de la Serna IL. 2024.. Targeting SWI/SNF complexes in cancer: pharmacological approaches and implications. . Epigenomes 8::7
     [Crossref] [Google Scholar]
  110. 110.
    Ordonez-Rubiano SC, Strohmier BP, Sood S, Dykhuizen EC. 2024.. SWI/SNF chromatin remodelers in prostate cancer progression. . Front. Epigenet. Epigenom. 1::1337345
     [Crossref] [Google Scholar]
  111. 111.
    Heebøll S, Borre M, Ottosen PD, Andersen CL, Mansilla F, et al. 2008.. SMARCC1 expression is upregulated in prostate cancer and positively correlated with tumour recurrence and dedifferentiation. . Histol. Histopathol. 23::1069–76
     [Google Scholar]
  112. 112.
    Cyrta J, Augspach A, De Filippo MR, Prandi D, Thienger P, et al. 2020.. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity. . Nat. Commun. 11::5549
     [Crossref] [Google Scholar]
  113. 113.
    Barma N, Stone TC, Carmona Echeverria LM, Heavey S. 2021.. Exploring the value of BRD9 as a biomarker, therapeutic target and co-target in prostate cancer. . Biomolecules 11::1794
     [Crossref] [Google Scholar]
  114. 114.
    Xiao L, Parolia A, Qiao Y, Bawa P, Eyunni S, et al. 2022.. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer. . Nature 601::434–39
     [Crossref] [Google Scholar]
  115. 115.
    Marshall TW, Link KA, Petre-Draviam CE, Knudsen KE. 2003.. Differential requirement of SWI/SNF for androgen receptor activity. . J. Biol. Chem. 278::30605–13
     [Crossref] [Google Scholar]
  116. 116.
    Link KA, Burd CJ, Williams E, Marshall T, Rosson G, et al. 2005.. BAF57 governs androgen receptor action and androgen-dependent proliferation through SWI/SNF. . Mol. Cell. Biol. 25::2200–15
     [Crossref] [Google Scholar]
  117. 117.
    Giles KA, Gould CM, Achinger-Kawecka J, Page SG, Kafer GR, et al. 2021.. BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer. . Clin. Epigenet. 13::37
     [Crossref] [Google Scholar]
  118. 118.
    Yang Z, Yik JH, Chen R, He N, Jang MK, et al. 2005.. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. . Mol. Cell 19::535–45
     [Crossref] [Google Scholar]
  119. 119.
    Mandal R, Becker S, Strebhardt K. 2021.. Targeting CDK9 for anti-cancer therapeutics. . Cancers 13::2181
     [Crossref] [Google Scholar]
  120. 120.
    Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG, et al. 2014.. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. . Genes Dev. 28::1800–14
     [Crossref] [Google Scholar]
  121. 121.
    Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, et al. 2010.. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. . Mol. Endocrinol. 24::2267–80
     [Crossref] [Google Scholar]
  122. 122.
    Richters A, Doyle SK, Freeman DB, Lee C, Leifer BS, et al. 2021.. Modulating androgen receptor-driven transcription in prostate cancer with selective CDK9 inhibitors. . Cell Chem. Biol. 28::134–47.e14
     [Crossref] [Google Scholar]
  123. 123.
    Xiao L, Liu Y, Chen H, Shen L. 2023.. Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments. . Cancer Biol. Ther. 24::2219470
     [Crossref] [Google Scholar]
  124. 124.
    Robb CM, Contreras JI, Kour S, Taylor MA, Abid M, et al. 2017.. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). . Chem. Commun. 53::7577–80
     [Crossref] [Google Scholar]
  125. 125.
    Qiu X, Li Y, Yu B, Ren J, Huang H, et al. 2021.. Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion. . Eur. J. Med. Chem. 211::113091
     [Crossref] [Google Scholar]
  126. 126.
    Hahn F, Hamilton ST, Wangen C, Wild M, Kicuntod J, et al. 2021.. Development of a PROTAC-based targeting strategy provides a mechanistically unique mode of anti-cytomegalovirus activity. . Int. J. Mol. Sci. 22::12858
     [Crossref] [Google Scholar]
  127. 127.
    Wu T, Zhang Z, Gong G, Du Z, Xu Y, et al. 2023.. Discovery of novel flavonoid-based CDK9 degraders for prostate cancer treatment via a PROTAC strategy. . Eur. J. Med. Chem. 260::115774
     [Crossref] [Google Scholar]
  128. 128.
    Bai S, Cao S, Jin L, Kobelski M, Schouest B, et al. 2019.. A positive role of c-Myc in regulating androgen receptor and its splice variants in prostate cancer. . Oncogene 38::4977–89
     [Crossref] [Google Scholar]
  129. 129.
    Noblejas-López MDM, Gandullo-Sánchez L, Galán-Moya EM, López-Rosa R, Tébar-García D, et al. 2022.. Antitumoral activity of a CDK9 PROTAC compound in HER2-positive breast cancer. . Int. J. Mol. Sci. 23::5476
     [Crossref] [Google Scholar]
  130. 130.
    Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, et al. 2001.. Delineation of prognostic biomarkers in prostate cancer. . Nature 412::822–26
     [Crossref] [Google Scholar]
  131. 131.
    Cibull TL, Jones TD, Li L, Eble JN, Baldridge LA, et al. 2006.. Overexpression of Pim-1 during progression of prostatic adenocarcinoma. . J. Clin. Pathol. 59::285–88
     [Crossref] [Google Scholar]
  132. 132.
    van der Poel HG, Zevenhoven J, Bergman AM. 2010.. Pim1 regulates androgen-dependent survival signaling in prostate cancer cells. . Urol. Int. 84::212–20
     [Crossref] [Google Scholar]
  133. 133.
    Xie Y, Bayakhmetov S. 2016.. PIM1 kinase as a promise of targeted therapy in prostate cancer stem cells. . Mol. Clin. Oncol. 4::13–17
     [Crossref] [Google Scholar]
  134. 134.
    Kim J, Roh M, Abdulkadir SA. 2010.. Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity. . BMC Cancer 10::248
     [Crossref] [Google Scholar]
  135. 135.
    Wang J, Kim J, Roh M, Franco OE, Hayward SW, et al. 2010.. Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma. . Oncogene 29::2477–87
     [Crossref] [Google Scholar]
  136. 136.
    Ha S, Iqbal NJ, Mita P, Ruoff R, Gerald WL, et al. 2013.. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer. . Oncogene 32::3992–4000
     [Crossref] [Google Scholar]
  137. 137.
    Ruff SE, Vasilyev N, Nudler E, Logan SK, Garabedian MJ. 2021.. PIM1 phosphorylation of the androgen receptor and 14-3-3ζ regulates gene transcription in prostate cancer. . Commun. Biol. 4::1221
     [Crossref] [Google Scholar]
  138. 138.
    Torres-Ayuso P, Katerji M, Mehlich D, Lookingbill SA, Sabbasani VR, et al. 2023.. PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer. . Cell Chem. Biol. 31:(2):326–37.e11
     [Crossref] [Google Scholar]
  139. 139.
    Kang HY, Lin HK, Hu YC, Yeh S, Huang KE, Chang C. 2001.. From transforming growth factor-β signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. . PNAS 98::3018–23
     [Crossref] [Google Scholar]
  140. 140.
    Lu S, Lee J, Revelo M, Wang X, Lu S, Dong Z. 2007.. Smad3 is overexpressed in advanced human prostate cancer and necessary for progressive growth of prostate cancer cells in nude mice. . Clin. Cancer Res. 13::5692–702
     [Crossref] [Google Scholar]
  141. 141.
    Buczek ME, Miles AK, Green W, Johnson C, Boocock DJ, et al. 2016.. Cytoplasmic PML promotes TGF-β-associated epithelial-mesenchymal transition and invasion in prostate cancer. . Oncogene 35::3465–75
     [Crossref] [Google Scholar]
  142. 142.
    Pal SK, Patel J, He M, Foulk B, Kraft K, et al. 2018.. Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC). . Cancer 124::1216–24
     [Crossref] [Google Scholar]
  143. 143.
    Guo H, Ci X, Ahmed M, Hua JT, Soares F, et al. 2019.. ONECUT2 is a driver of neuroendocrine prostate cancer. . Nat. Commun. 10::278
     [Crossref] [Google Scholar]
  144. 144.
    Jeon H-Y, Pornour M, Ryu H, Khadka S, Xu R, et al. 2023.. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer. . Nucleic Acids Res. 51::2655–70
     [Crossref] [Google Scholar]
  145. 145.
    Wang X, Feng S, Fan J, Li X, Wen Q, Luo N. 2016.. New strategy for renal fibrosis: targeting Smad3 proteins for ubiquitination and degradation. . Biochem. Pharmacol. 116::200–9
     [Crossref] [Google Scholar]
  146. 146.
    Moreau K, Coen M, Zhang AX, Pachl F, Castaldi MP, et al. 2020.. Proteolysis-targeting chimeras in drug development: a safety perspective. . Br. J. Pharmacol. 177::1709–18
     [Crossref] [Google Scholar]
  147. 147.
    Garber K. 2022.. The PROTAC gold rush. . Nat. Biotechnol. 40::12–16
     [Crossref] [Google Scholar]
  148. 148.
    Chen Y, Tandon I, Heelan W, Wang Y, Tang W, Hu Q. 2022.. Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation. . Chem. Soc. Rev. 51::5330–50
     [Crossref] [Google Scholar]
  149. 149.
    Liu Y, Yang J, Wang T, Luo M, Chen Y, et al. 2023.. Expanding PROTACtable genome universe of E3 ligases. . Nat. Commun. 14::6509
     [Crossref] [Google Scholar]
  150. 150.
    Toriki ES, Papatzimas JW, Nishikawa K, Dovala D, Frank AO, et al. 2023.. Rational chemical design of molecular glue degraders. . ACS Cent. Sci. 9::915–26
     [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-030624-110238
Loading
PROTACs as Therapeutic Modalities for Drug Discovery in Castration-Resistant Prostate Cancer
Annual Review of Pharmacology and Toxicology 65, 375 (2025); https://doi.org/10.1146/annurev-pharmtox-030624-110238
/content/journals/10.1146/annurev-pharmtox-030624-110238
/content/journals/10.1146/annurev-pharmtox-030624-110238
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error