The ubiquitin-proteasome system plays a central role in regulating protein homeostasis in mammalian cells. It is a multistep process involving the polyubiquitination of proteins prior to their proteolytic degradation by the 26S proteasome complex. Blockade of this process results in the accumulation of proteins that are deleterious to the survival of cancer cells and has led to the approval of the proteasome inhibitors bortezomib and carfilzomib for the treatment of multiple myeloma and mantle cell lymphoma. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to recruit an E3 ubiquitin ligase to a specific target protein, thereby providing a mechanism to ubiquitinate and degrade specific pathological proteins. A significant body of preclinical data, generated since PROTACs were first introduced 15 years ago, demonstrates that PROTACs provide a robust approach to expose new cell biology and to generate novel therapeutics with the potential to target currently undruggable proteins.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Aghajan M, Jonai N, Flick K, Fu F, Luo M. et al. 2010. Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase. Nat. Biotechnol. 28:738–42 [Google Scholar]
  2. 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 [Google Scholar]
  3. Bai L, Zhou B, Yang C-Y, Jai J, McEachern D. et al. 2017. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res 77:2476–87 [Google Scholar]
  4. Baratta MG, Schinzel AC, Zwang Y, Bandopadhayay P, Bowman-Colin C. et al. 2015. An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma. PNAS 112:232–37 [Google Scholar]
  5. Bartlett JB, Dredge K, Dalgleish AG. 2004. Timeline: the evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4:314–22 [Google Scholar]
  6. Belkina AC, Denis G. 2012. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer 12:465–77 [Google Scholar]
  7. Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E. et al. 2015. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin. Cancer Res. 21:1628–38 [Google Scholar]
  8. Bondeson DP, Mares A, Smith IE, Ko E, Campos S. et al. 2015. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11:611–17 [Google Scholar]
  9. Bowler J, Lilley TJ, Pittam JD, Wakeling AE. 1989. Novel steroidal pure antiestrogens. Steroids 54:71–99 [Google Scholar]
  10. Bruick RK, McKnight SL. 2001. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–40 [Google Scholar]
  11. Buckley DL, Gustafson JL, Van Molle I Roth AG, Tae HS. et al. 2012.a Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew. Chem. Int. Ed. 51:11463–67 [Google Scholar]
  12. Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL. et al. 2015. HaloPROTACs: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins. ACS Chem. Biol. 10:1831–37 [Google Scholar]
  13. Buckley DL, Van Molle I, Gareiss PC, Tae HS, Michel J. et al. 2012.b Targeting the von Hippel–Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J. Am. Chem. Soc. 134:4465–68 [Google Scholar]
  14. Bus. Wire. 2016. C4 Therapeutics launches with $73 million series A financing. Bus. Wire Jan. 7. http://www.businesswire.com/news/home/20160107005259/en/C4-Therapeutics-Launches-73-Million-Series-Financing
  15. Cao B, Qi Y, Zhang G, Xu D, Zhan Y. et al. 2014. Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5:1646–56 [Google Scholar]
  16. Carroll J. 2015. Genentech embraces Arvinas with $300M tie-up on protein degradation. FierceBiotech Oct. 15. http://www.fiercebiotech.com/biotech/genentech-embraces-arvinas-300m-tie-up-on-protein-degradation
  17. Chan CH, Morrow JK, Li CF, Gao Y, Jin G. et al. 2013. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 154:556–58 [Google Scholar]
  18. Chapuy B, McKeown M, Lin C, Monti S, Roemer M. et al. 2013. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24:777–90 [Google Scholar]
  19. Chu TT, Gao N, Li QQ, Chen PG, Yang XF. et al. 2016. Specific knockdown of endogenous Tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem. Biol. 23:453–61 [Google Scholar]
  20. Cong L, Ran FA, Cox D, Lin S, Barretto R. et al. 2013. Multiplex genome engineering using CRISPR/Cas system. Science 339:819–24 [Google Scholar]
  21. Crews CM, Buckley D, Ciulli A, Jorgensen W, Gareiss PC. et al. 2013. Compounds and methods for the inhibition of VCB E3 ubiquitin ligase US Patent No. WO2013106646A2
  22. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J. et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–17 [Google Scholar]
  23. Demizu Y, Shibata N, Hattori T, Ohoka N, Motoi H. et al. 2016. Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Bioorg. Med. Chem. Lett. 26:4865–69 [Google Scholar]
  24. Donovan M, Olofsson B, Gustafson AL, Dencker L, Eriksson U. 1995. The cellular retinoic acid binding proteins. J. Steroid Biochem. Mol. Biol. 53:459–65 [Google Scholar]
  25. Douglass EF, Miller CJ, Sparer G, Shapiro H, Spiegel DA. 2013. A comprehensive mathematical model for three-body binding equilibria. J. Am. Chem. Soc. 135:6092–99 [Google Scholar]
  26. Eder IE, Culig Z, Ramoner R, Thurnher M, Putz T. et al. 2007. Inhibition of LNCaP prostate cancer cells by means of androgen receptor antisense oligonucleotides. Cancer Gene Ther 7:997–1007 [Google Scholar]
  27. Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB. et al. 2014. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512:49–53 [Google Scholar]
  28. Fogh K, Voorhees JJ, Astrom A. 1993. Expression, purification, and binding properties of human cellular retinoic acid-binding protein type I and type II. Arch. Biochem. Biophys. 300:751–55 [Google Scholar]
  29. French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ. et al. 2008. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27:2237–42 [Google Scholar]
  30. Fulda S, Vucic D. 2012. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov. 11:109–24 [Google Scholar]
  31. Gadd MS, Testa A, Lucas X, Chan KH, Chen W. et al. 2017. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13:514–21 [Google Scholar]
  32. Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y. et al. 2014. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN. Br. J. Haematol. 164:811–21 [Google Scholar]
  33. Garde D. 2015. Merck wagers $434M on Arvinas and its protein-disposal system. FierceBiotech April. http://www.fiercebiotech.com/partnering/merck-wagers-434m-on-arvinas-and-its-protein-disposal-system
  34. Griffith EC, Su Z, Turk BE, Chen S, Chang YHH. et al. 1997. Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin. Chem. Biol. 4:461–71 [Google Scholar]
  35. Gupta A, Kessler P, Rawwas J, Williams BRG. 2008. Regulation of CRABP-II expression by MycN in Wilms tumor. Exp. Cell Res. 314:3663–68 [Google Scholar]
  36. Gupta A, Williams BRG, Hanash SM, Rawwas J. 2006. Cellular retinoic acid-binding protein II is a direct transcriptional target of MycN in neuroblastoma. Cancer Res 66:8100–8 [Google Scholar]
  37. Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL. et al. 2015. Small-molecule-mediated degradation of the androgen receptor through hydrophobic tagging. Angew. Chem. Int. Ed. 54:9659–62 [Google Scholar]
  38. Hellyer NJ, Kim MS, Koland JG. 2001. Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J. Biol. Chem. 276:42153–61 [Google Scholar]
  39. Hines J, Gough JD, Corson TW, Crews CM. 2013. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. PNAS 110:8942–47 [Google Scholar]
  40. Hochstrasser M. 1995. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr. Opin. Cell Biol. 7:215–23 [Google Scholar]
  41. Hon W, Wilson M, Harlos K, Claridge TDW, Schofield CJ. et al. 2002. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417:975–78 [Google Scholar]
  42. Infante JR, Dees EC, Olszanski AJ, Dhruia SV, Sen S. et al. 2014. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 32:3103–10 [Google Scholar]
  43. Ito T, Ando H, Suzuki T, Ogura T, Hotta K. et al. 2010. Identification of a primary target of thalidomide teratogenicity. Science 327:1345–50 [Google Scholar]
  44. Itoh Y, Ishikawa M, Kitaguchi R, Okuhira K, Naito M, Hashimoto Y. 2012. Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist. Bioorg. Med. Chem. Lett. 22:4453–57 [Google Scholar]
  45. Itoh Y, Ishikawa M, Naito M, Hashimoto Y. 2010. Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J. Am. Chem. Soc. 132:5820–26 [Google Scholar]
  46. Jeng JC, Lin YM, Lin CH, Shih HM. 2009. Cdh1 controls the stability of TACC3. Cell Cycle 8:3529–36 [Google Scholar]
  47. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. 2012. A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–22 [Google Scholar]
  48. Kleiner RE, Dumelin CE, Liu DR, Stockwell BR, Kaddurah-Daouk R. et al. 2011. Small-molecule discovery from DNA-encoded chemical libraries. Chem. Soc. Rev. 40:5707–17 [Google Scholar]
  49. Krönke J, Fink EC, Hollenbach PW, Macbeth KJ, Hurst SN. et al. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:183–88 [Google Scholar]
  50. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN. et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5 [Google Scholar]
  51. Kubota H. 2009. Quality control against misfolded proteins in the cytosol: a network for cell survival. J. Biochem. 146:609–16 [Google Scholar]
  52. Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figeroa S. et al. 2016. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. 55:807–10 [Google Scholar]
  53. Liao X, Tang S, Thrasher JB, Griebling TL, Li B. 2005. Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol. Cancer Ther. 4:505–15 [Google Scholar]
  54. Lim SM, Xie T, Westover KD, Ficarro SB, Tae HS. et al. 2015. Development of small molecules targeting the pseudokinase Her3. Bioorg. Med. Chem. Lett. 25:3382–89 [Google Scholar]
  55. Linja MJ, Savinainen KJ, Saramäki OR, Tammela TL, Vessella RL, Visakorpi T. 2001. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61:3550–55 [Google Scholar]
  56. Lins L, Brasseur R. 1995. The hydrophobic effect in protein folding. FASEB J 9:535–40 [Google Scholar]
  57. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 23:3–25 [Google Scholar]
  58. Long MJC, Gollapalli DR, Hedstrom L. 2012. Inhibitor mediated protein degradation. Chem. Biol. 19:629–37 [Google Scholar]
  59. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK. et al. 2012. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26:2326–35 [Google Scholar]
  60. Los GV, Encell LP, McDougall MG, Hartzell DD, Karassina N. et al. 2008. HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem. Biol. 3:373–82 [Google Scholar]
  61. Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA. et al. 2013. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320–34 [Google Scholar]
  62. Lu G, Middleton RE, Sun H, Naniong M, Christopher J. et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9 [Google Scholar]
  63. Lu J, Qian Y, Altieri M, Dong H, Wang J. et al. 2015. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22:755–63 [Google Scholar]
  64. Maculins T, Carter N, Dorval T, Hudson K, Nissink JWM. et al. 2016. A generic platform for cellular screening against ubiquitin ligases. Sci. Rep. 6:18940 [Google Scholar]
  65. Marhefka CA, Gao W, Chung K, Kim J, He Y. et al. 2004. Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators. J. Med. Chem. 47:993–98 [Google Scholar]
  66. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC. et al. 2016. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535:252–57 [Google Scholar]
  67. Meakin SO, MacDonald JIS, Gryz EA, Kubu CJ, Verdi JM. 1999. The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA: a model for discriminating proliferation and differentiation. J. Biol. Chem. 274:9861–70 [Google Scholar]
  68. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S. et al. 2011. Targeting MYC dependence in cancer by inhibiting BET bromodomains. PNAS 108:16669–74 [Google Scholar]
  69. Metzger MB, Hristova VA, Weissman AM. 2012. HECT and RING finger families of E3 ubiquitin ligases at a glance. J. Cell Sci. 125:531–37 [Google Scholar]
  70. Mughal A, Aslam HM, Khan AMH, Saleem S, Umah R, Saleem M. 2013. Bcr-Abl tyrosine kinase inhibitors: current status. Infect. Agents Cancer 8:23 [Google Scholar]
  71. Navon A, Ciechanover A. 2009. The 26S proteasome: from basic mechanisms to drug targeting. J. Biol. Chem. 284:33713–18 [Google Scholar]
  72. Neklesa TK, Tae HS, Schneekloth AR, Stulberg MJ, Corson TW. et al. 2011. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7:538–43 [Google Scholar]
  73. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY. et al. 2000. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nat. Cell Biol. 2:423–27 [Google Scholar]
  74. Ohoka N, Nagai K, Hattori T, Okuhira K, Shibata N. et al. 2014. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway. Cell Death Dis 5:e1513 [Google Scholar]
  75. Ohoka N, Okuhira K, Ito M, Nagai K, Shibata N. et al. 2017. In vivo knockdown of pathogenic proteins via specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs). J. Biol. Chem. 292:4556–70 [Google Scholar]
  76. Okuhira K, Demizu Y, Hattori T, Ohoka N, Shibata N. et al. 2013. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci 104:1492–98 [Google Scholar]
  77. Okuhira K, Ohoka N, Sai K, Nishimaki-Mogami T, Itoh Y. et al. 2011. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett 585:1147–52 [Google Scholar]
  78. Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N. et al. 2000. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Mol. Cell. Biol. 20:979–89 [Google Scholar]
  79. Orlicky S, Tang X, Neduva V, Elowe N, Brown ED. et al. 2010. An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase. Nat. Biotechnol. 28:733–37 [Google Scholar]
  80. Peters JM. 2006. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell. Biol. 7:644–56 [Google Scholar]
  81. Piette J, Neel H, Marechal V. 1997. Mdm2: keeping p53 under control. Oncogene 15:1001–10 [Google Scholar]
  82. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J. et al. 2013. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov 3:309–23 [Google Scholar]
  83. 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 [Google Scholar]
  84. Rayburn ER, Zhang R. 2008. Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?. Drug Discov. Today 13:513–21 [Google Scholar]
  85. 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 [Google Scholar]
  86. Rollins CT, Rivera VM, Woolfson DN, Keenan T, Hatada M. et al. 2000. A ligand-reversible dimerization system for controlling protein–protein interactions. PNAS 97:7096–101 [Google Scholar]
  87. Russ AP, Lampel S. 2005. The druggable genome: an update. Drug Discov. Today 10:1607–10 [Google Scholar]
  88. Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K. et al. 2017. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 31:1951–61 [Google Scholar]
  89. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. 2001. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. PNAS 98:8554–59 [Google Scholar]
  90. Sakamoto KM, Kim KB, Verma R, Mercurio F, Crews CM. et al. 2003. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteom. 2:1350–58 [Google Scholar]
  91. Sato S, Aoyama H, Miyachi H, Naito M, Hashimoto Y. 2008. Demonstration of direct binding of cIAP1 degradation-promoting bestatin analogs to BIR3 domain: synthesis and application of fluorescent bestatin ester analogs. Bioorg. Med. Chem. Lett. 18:3354–58 [Google Scholar]
  92. Schlessinger J, Lemmon MA. 2003. SH2 and PTB domains in tyrosine kinase signaling. Sci. STKE 2003:RE12 [Google Scholar]
  93. 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 [Google Scholar]
  94. Schneekloth JS, 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 [Google Scholar]
  95. Sekine K, Takubo K, Kikuchi R, Nishimoto M, Kitagawa M. et al. 2008. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J. Biol. Chem. 283:8961–68 [Google Scholar]
  96. Shi J, Vakoc CR. 2014. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol. Cell 54:728–36 [Google Scholar]
  97. Shi Y, Long MJC, Rosenberg MM, Li S, Kobjack A. et al. 2016. Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS Chem. Biol. 11:3328–37 [Google Scholar]
  98. Sin N, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM. 1997. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. PNAS 94:6099–103 [Google Scholar]
  99. Taylor NP. 2016. Boehringer strikes deal to develop protein-degrading cancer drugs. FierceBiotech July. http://www.fiercebiotech.com/biotech/boehringer-strikes-deal-to-develop-protein-degrading-cancer-drugs
  100. Van Molle I, Thomann A, Buckley DL, So EC, Lang S. et al. 2012. Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface. Chem. Biol. 19:1300–12 [Google Scholar]
  101. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N. et al. 2007. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131:669–81 [Google Scholar]
  102. Vassilev LT, Vu BT, Craves B, Carvajal D, Podlaski F. et al. 2004. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–48 [Google Scholar]
  103. Vo HP, Crowe DL. 1998. Transcriptional regulation of retinoic acid responsive genes by cellular retinoic acid binding protein-II modulates RA mediated tumor cell proliferation and invasion. Anticancer Res 18:217–24 [Google Scholar]
  104. Wang GL, Jiang BH, Rue EA, Semenza GL. 1995. Hypoxia-inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. PNAS 92:5510–14 [Google Scholar]
  105. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND. et al. 2010. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. PNAS 107:16759–65 [Google Scholar]
  106. Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A. et al. 2015. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348:1376–81 [Google Scholar]
  107. Wittmann BM, Sherk A, McDonnell DP. 2007. Definition of functionally important mechanistic differences among selective estrogen receptor down-regulators. Cancer Res 67:9549–60 [Google Scholar]
  108. 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 [Google Scholar]
  109. Wyce A, Degenhardt Y, Bai Y, Le BC, Korenchuk S. et al. 2013. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4:2419–29 [Google Scholar]
  110. Xie T, Lim SM, Westover KD, Dodge ME, Ercan D. et al. 2014. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 10:1006–12 [Google Scholar]
  111. Xu D, Zhan Y, Qi Y, Cao B, Bai S. et al. 2015. Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res 75:3663–71 [Google Scholar]
  112. Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. 2002. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res 62:1008–13 [Google Scholar]
  113. Zhang D, Baek SH, Ho A, Kim K. 2004. Degradation of target protein in living cells by small-molecule proteolysis inducer. Bioorganic Med. Chem. Lett. 14:645–48 [Google Scholar]
  114. Zuber JJ, Shi JJ, Wang EE, Rappaport ARAR, Hermann HH. et al. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–28 [Google Scholar]

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
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