Targeted protein knockdown using small molecule degraders

Current Opinion in Chemical Biology

Volumn 39, Issue , 2017, Pages 46-53

  Raina, Kanak ^a   Crews, Craig M ^b,c  

^a Arvinas Inc   (United States)

^b YALE UNIVERSITY   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL PROTEIN; CULLIN; IAP PROTEIN; PROTEIN; PROTEIN MDM2; UNCLASSIFIED DRUG; VON HIPPEL LINDAU PROTEIN; MOLECULAR LIBRARY;

CHEMICAL GENETICS; HYDROPHOBICITY; MOLECULAR LIBRARY; MOLECULE; NONHUMAN; PROTEIN DEGRADATION; PROTEIN TARGETING; REVIEW; AMINO ACID SEQUENCE; ANIMAL; CHEMISTRY; DRUG EFFECTS; HUMAN; METABOLISM; PHARMACOLOGY;

AMINO ACID SEQUENCE; ANIMALS; HUMANS; PROTEINS; PROTEOLYSIS; SMALL MOLECULE LIBRARIES;

EID: 85020454226     PISSN: 13675931     EISSN: 18790402     Source Type: Journal    
DOI: 10.1016/j.cbpa.2017.05.016     Document Type: Review

References (54)

1. 1 Smietana, K., Siatkowski, M., Møller, M., Trends in clinical success rates. Nat Rev Drug Discov 15 (2016), 379–380.
2. 2 Mitragotri, S., Burke, P.A., Langer, R., Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat Rev Drug Discov 13 (2014), 655–672.
3. 3 Lundin, K.E., Gissberg, O., Smith, C.I.E., Oligonucleotide therapies: the past and the present. Hum Gene Ther 26 (2015), 475–485.
4. 4 Burnett, J.C., Rossi, J.J., RNA-based therapeutics: current progress and future prospects. Chem Biol 19 (2012), 60–71.
5. 5 Fellmann, C., Gowen, B.G., Lin, P-C., Doudna, J.A., Corn, J.E., Cornerstones of CRISPR–Cas in drug discovery and therapy. Nat Rev Drug Discov, 2016, 10.1038/nrd.2016.238.
6. 6• BIO, Clinical development success rates 2006–2015. Report, 2016, 10.1038/nrd.2016.85 The authors compare the performances of all therpeutic modalities in the clinic over a 10-year period.
7. 7 Lazo, J.S., Sharlow, E.R., Drugging undruggable molecular cancer targets. Annu Rev Pharmacol Toxicol 56 (2016), 23–40.
8. 8 Adjei, A.A., What is the right dose? The elusive optimal biologic dose in phase I clinical trials. J Clin Oncol 24 (2006), 4054–4055.
9. 9 Schall, T.J., Proudfoot, A.E.I., Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat Rev Immunol 11 (2011), 355–363.
10. 10 Li, W., Bengtson, M.H., Ulbrich, A., Matsuda, A., Reddy, V.A., Orth, A., Chanda, S.K., Batalov, S., Joazeiro, C.A.P., Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS ONE, 3, 2008, e1487.
11. 11•• Bondeson, D.P., Mares, A., Smith, I.E.D., Ko, E., Campos, S., Miah, A.H., Mulholland, K.E., Routly, N., Buckley, D.L., Gustafson, J.L., et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol 11 (2015), 611–617 The authors conduct a biochemical investigation of the catalytic property of PROTACs.
12. 12 Skaar, J.R., Pagan, J.K., Pagano, M., SCF ubiquitin ligase-targeted therapies. Nat Rev Drug Discov 13 (2014), 889–903.
13. 13 Lucas, X., Ciulli, A., Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies. Curr Opin Struct Biol 44 (2017), 101–110.
14. 14 Sakamoto, K.M., Kim, K.B., Kumagai, A., Mercurio, F., Crews, C.M., Deshaies, R.J., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A 98 (2001), 8554–8559.
15. 15 Sakamoto, K.M., Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol Cell Proteomics 2 (2003), 1350–1358.
16. 16•• Schneekloth, J.S., Fonseca, F.N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K., Crews, C.M., Chemical genetic control of protein levels: selective in vivo targeted degradation. J Am Chem Soc 126 (2004), 3748–3754 The first description of an ‘all small molecule’ PROTAC.
17. 17 Tang, Y-Q., Han, B-M., Yao, X-Q., Hong, Y., Wang, Y., Zhao, F-J., Yu, S-Q., Sun, X-W., Xia, S-J., Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells. Asian J Androl 11 (2009), 119–126.
18. 18 Montrose, K., Krissansen, G.W., Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus. Biochem Biophys Res Commun 453 (2014), 735–740.
19. 19 Lee, H., Puppala, D., Choi, E.Y., Swanson, H., Kim, K.B., Targeted degradation of the aryl hydrocarbon receptor by the PROTAC approach: a useful chemical genetic tool. ChemBioChem 8 (2007), 2058–2062.
20. 20 Puppala, D., Lee, H., Kim, K.B., Swanson, H.I., Development of an aryl hydrocarbon receptor antagonist using the proteolysis-targeting chimeric molecules approach: a potential tool for chemoprevention. Mol Pharmacol 73 (2008), 1064–1071.
21. 21 Bargagna-Mohan, P., Baek, S.H., Lee, H., Kim, K., Mohan, R., Use of PROTACS as molecular probes of angiogenesis. Bioorg Med Chem Lett 15 (2005), 2724–2727.
22. 22 Cyrus, K., Wehenkel, M., Choi, E.Y., Lee, H., Swanson, H., Kim, K.B., Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem 5 (2010), 979–985.
23. 23 Hines, J., Gough, J.D., Corson, T.W., Crews, C.M., Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc Natl Acad Sci U S A 110 (2013), 8942–8947.
24. 24 Schneekloth, A.R., Pucheault, M., Tae, H.S., Crews, C.M., Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg Med Chem Lett 18 (2008), 5904–5908.
25. 25 Okuhira, K., Ohoka, N., Sai, K., Nishimaki-Mogami, T., Itoh, Y., Ishikawa, M., Hashimoto, Y., Naito, M., Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett 585 (2011), 1147–1152.
26. 26 Demizu, Y., Okuhira, K., Motoi, H., Ohno, A., Shoda, T., Fukuhara, K., Okuda, H., Naito, M., Kurihara, M., Design and Synthesis of Estrogen Receptor Degradation Inducer Based on a Protein Knockdown Strategy. 2012.
27. 27 Okuhira, K., Demizu, Y., Hattori, T., Ohoka, N., Shibata, N., Nishimaki-Mogami, T., Okuda, H., Kurihara, M., Naito, M., Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci 104 (2013), 1492–1498.
28. 28 Ohoka, N., Nagai, K., Hattori, T., Okuhira, K., Shibata, N., Cho, N., Naito, M., Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway. Cell Death Dis, 5, 2014, e1513.
29. 29 Sekine, K., Takubo, K., Kikuchi, R., Nishimoto, M., Kitagawa, M., Abe, F., Nishikawa, K., Tsuruo, T., Naito, M., Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J Biol Chem 283 (2008), 8961–8968.
30. 30• Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. In vivo knockdown of pathogenic proteins via specific and nongenetic IAP-dependent protein erasers (SNIPERs). J Biol Chem, 2017, 10.1074/jbc.M116.768853 The authors describe highly optimized IAP based PROTACs with in vivo activity.
31. 31 Buckley, D.L., Van Molle, I., Gareiss, P.C., Tae, H.S., Michel, J., Noblin, D.J., Jorgensen, W.L., Ciulli, A., Crews, C.M., Targeting the von Hippel–Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J Am Chem Soc 134 (2012), 4465–4468.
32. 32 Buckley, D.L., Gustafson, J.L., Van Molle, I., Roth, A.G., Tae, H.S., Gareiss, P.C., Jorgensen, W.L., Ciulli, A., Crews, C.M., Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew Chem Int Ed 51 (2012), 11463–11467.
33. 33 Frost, J., Galdeano, C., Soares, P., Gadd, M.S., Grzes, K.M., Ellis, L., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., et al. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat Commun, 7, 2016, 13312.
34. 34 Buckley, D.L., Raina, K., Darricarrere, N., Hines, J., Gustafson, J.L., Smith, I.E., Miah, A.H., Harling, J.D., Crews, C.M., HaloPROTACS: use of small molecule PROTACs to induce degradation of halotag fusion proteins. ACS Chem Biol 10 (2015), 1831–1837.
35. 35 Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., Handa, H., Identification of a primary target of thalidomide teratogenicity. Science 327 (2010), 1345–1350.
36. 36 Lu, G., Middleton, R.E., Sun, H., Naniong, M., Ott, C.J., Mitsiades, C.S., Wong, K-K., Bradner, J.E., Kaelin, W.G., The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343 (2014), 305–309.
37. 37 Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J.D., Crew, A.P., Coleman, K., et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol 22 (2015), 755–763.
38. 38 Winter, G.E., Buckley, D.L., Paulk, J., Roberts, J.M., Souza, A., Dhe-Paganon, S., Bradner, J.E., Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348 (2015), 1376–1381.
39. 39 Zengerle, M., Chan, K-H., Ciulli, A., Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem Biol 10 (2015), 1770–1777.
40. 40•• Gadd, M., Testa, A., Lucas, X., Chan, K., Chen, W., Lamont, D., Zengerle, M., Ciulli, A., Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol, 2017, 10.2210/PDB5T35/PDB Armed with a E3::PROTAC::POI trimer crystal structure, the authors provide a biophysical explanation for the exquisite selectivity and potency of PROTACs.
41. 41 Lai, A.C., Toure, M., Hellerschmied, D., Salami, J., Jaime-Figueroa, S., Ko, E., Hines, J., Crews, C.M., Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed 55 (2016), 807–810.
42. 42•• Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A.M., Wang, J., Chen, X., Dong, H., Siu, K., et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A 113 (2016), 7124–7129 The authors provide the first instance of a PROTAC active in vivo via a clinically viable route of administration.
43. 43 Bai, L., Zhou, B., Yang, C-Y., Ji, J., McEachern, D., Przybranowski, S., Jiang, H., Hu, J., Xu, F., Zhao, Y., et al. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res, 2017, 10.1158/0008-5472.CAN-16-2622.
44. 44•• Shu, S., Lin, C.Y., He, H.H., Witwicki, R.M., Tabassum, D.P., Roberts, J.M., Janiszewska, M., Jin Huh, S., Liang, Y., Ryan, J., et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature, 2016, 10.1038/nature16508 The authors propose a bromodomain independent and inhibitor resistant activity for BET proteins.
45. 45 Wittmann, B.M., Sherk, A., McDonnell, D.P., Definition of functionally important mechanistic differences among selective estrogen receptor down-regulators. Cancer Res, 67, 2007.
46. 46 McDonnell, D.P., Wardell, S.E., Norris, J.D., Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J Med Chem 58 (2015), 4883–4887.
47. 47 Loddick, S.A., Ross, S.J., Thomason, A.G., Robinson, D.M., Walker, G.E., Dunkley, T.P.J., Brave, S.R., Broadbent, N., Stratton, N.C., Trueman, D., et al. AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. Mol Cancer Ther, 12, 2013.
48. 48 Omlin, A., Jones, R.J., van der Noll, R., Satoh, T., Niwakawa, M., Smith, S.A., Graham, J., Ong, M., Finkelman, R.D., Schellens, J.H.M., et al. AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer — results of two parallel first-in-human phase I studies. Investig New Drugs 33 (2015), 679–690.
49. 49 Williams, R., Discontinued drugs in 2012: oncology drugs. Expert Opin Investig Drugs 22 (2013), 1627–1644.
50. 50 Citri, A., Alroy, I., Lavi, S., Rubin, C., Xu, W., Grammatikakis, N., Patterson, C., Neckers, L., Fry, D.W., Yarden, Y., Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO J 21 (2002), 2407–2417.
51. 51 Gustafson, J.L., Neklesa, T.K., Cox, C.S., Roth, A.G., Buckley, D.L., Tae, H.S., Sundberg, T.B., Stagg, D.B., Hines, J., McDonnell, D.P., et al. Small-molecule-mediated degradation of the androgen receptor through hydrophobic tagging. Angew Chem Int Ed 54 (2015), 9659–9662.
52. 52 Xie, T., Lim, S.M., Westover, K.D., Dodge, M.E., Ercan, D., Ficarro, S.B., Udayakumar, D., Gurbani, D., Tae, H.S., Riddle, S.M., et al. Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol 10 (2014), 1006–1012.
53. 53 Long, M.J.C., Gollapalli, D.R., Hedstrom, L., Inhibitor mediated protein degradation. Chem Biol 19 (2012), 629–637.
54. 54• Shi, Y., Long, M.J.C., Rosenberg, M.M., Li, S., Kobjack, A., Lessans, P., Coffey, R.T., Hedstrom, L., Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS Chem Biol, 2016, 10.1021/acschembio.6b00656 The authors describe the unique mechanism of Boc3Arg mediated degradation in cells.