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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2020 | Review

Proteolysis targeting chimeras (PROTACs) in cancer therapy

Authors: Alberto Ocaña, Atanasio Pandiella

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Abstract

Exploitation of the protein degradation machinery as a therapeutic strategy to degrade oncogenic proteins is experiencing revolutionary advances with the development of proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional structures consisting of a ligand that binds a protein to be degraded and a ligand for an E3 ubiquitin ligase. The bridging between the protein of interest and the E3 ligase mediated by the PROTAC facilitates ubiquitination of the protein and its proteasomal degradation. In this review we discuss the molecular medicine behind PROTAC mechanism of action, with special emphasis on recent developments and their potential translation to the clinical setting.

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Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMed

Ocana A, et al. Refining early Antitumoral drug development. Trends Pharmacol Sci. 2018;39:922–5.PubMedCrossRef

Schapira M, et al. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18:949–63.PubMedCrossRef

Inobe T, Matouschek A. Paradigms of protein degradation by the proteasome. Curr Opin Struct Biol. 2014;24:156–64.PubMedCrossRef

An S, Fu L. Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs. EBioMedicine. 2018;36:553–62.PubMedPubMedCentralCrossRef

Bushweller JH. Targeting transcription factors in cancer - from undruggable to reality. Nat Rev Cancer. 2019;19:611–24.PubMedCrossRefPubMedCentral

Chen A, Koehler A. Transcription Factor Inhibition: Lessons Learned and Emerging Targets. 2020. https://doi.org/10.1016/j.molmed.2020.01.004.

Yu J-M, et al. TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nat Commun. 2019;10:5720.PubMedPubMedCentralCrossRef

Mullard A. Arvinas’s PROTACs pass first safety and PK analysis. Nat Rev Drug Discov. 2019;18:895.PubMed

10.

Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818–22.PubMedCrossRef

11.

Bard JAM, et al. The 26S proteasome utilizes a kinetic gateway to prioritize substrate degradation. Cell. 2019;177:286–98 e15.PubMedPubMedCentralCrossRef

12.

Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 2020;21:101–18.PubMedCrossRef

13.

Dvela-Levitt M, et al. Small molecule targets TMED9 and promotes Lysosomal degradation to reverse Proteinopathy. Cell. 2019;178:521–35 e23.PubMedCrossRef

14.

Bard JAM, et al. Structure and function of the 26S proteasome. Annu Rev Biochem. 2018;87:697–724.PubMedPubMedCentralCrossRef

15.

Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat. Rev. Mol. Cell Biol. 2008;9:679–90.PubMedPubMedCentralCrossRef

16.

Thrower JS, et al. Recognition of the polyubiquitin proteolytic signal. EMBO J. 2000;19:94–102.PubMedPubMedCentralCrossRef

17.

Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503–33.PubMedCrossRef

18.

Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10:319–31.PubMedPubMedCentralCrossRef

19.

Popow J, et al. Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions. J Med Chem. 2019;62:2508–20.PubMedCrossRef

20.

van Wijk SJL, Timmers HTM. The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins. FASEB J Off Publ Fed Am Soc Exp Biol. 2010;24:981–93.

21.

Metzger MB, et al. HECT and RING finger families of E3 ubiquitin ligases at a glance. J Cell Sci. 2012;125:531–7.PubMedPubMedCentralCrossRef

22.

Skaar JR, Pagano M. Control of cell growth by the SCF and APC/C ubiquitin ligases. Curr Opin Cell Biol. 2009;21:816–24.PubMedPubMedCentralCrossRef

23.

Zheng N, Shabek N. Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem. 2017;86:129–57.PubMedCrossRef

24.

Sakamoto KM, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001;98:8554–9.PubMedPubMedCentralCrossRef

25.

Schneekloth AR, et al. Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg Med Chem Lett. 2008;18:5904–8.PubMedCrossRef

26.

Van Molle I, et al. Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1alpha protein-protein interface. Chem Biol. 2012;19:1300–12.PubMedPubMedCentralCrossRef

27.

Galdeano C, et al. Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. J Med Chem. 2014;57:8657–63.PubMedPubMedCentralCrossRef

28.

Soares P, et al. Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298). J Med Chem. 2018;61:599–618.PubMedCrossRef

29.

Bargagna-Mohan P, et al. Use of PROTACS as molecular probes of angiogenesis. Bioorg Med Chem Lett. 2005;15:2724–7.PubMedPubMedCentralCrossRef

30.

Sakamoto KM, et al. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics MCP. 2003;2:1350–8.PubMedCrossRef

31.

Winter GE, et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–81.PubMedPubMedCentralCrossRef

32.

Bondeson DP, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11:611–7.PubMedPubMedCentralCrossRef

33.

Zengerle M, et al. Selective small molecule induced degradation of the BET Bromodomain protein BRD4. ACS Chem Biol. 2015;10:1770–7.PubMedPubMedCentralCrossRef

34.

Lu J, et al. Hijacking the E3 ubiquitin ligase Cereblon to efficiently target BRD4. Chem Biol. 2015;22:755–63.PubMedPubMedCentralCrossRef

35.

Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.PubMedPubMedCentralCrossRef

36.

Shi C, et al. PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis. Cell Death Dis. 2019;10:815.PubMedPubMedCentralCrossRef

37.

Qin C, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the Bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J Med Chem. 2018;61:6685–704.PubMedPubMedCentralCrossRef

38.

Noblejas-Lopez MDM, et al. Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res CR. 2019;38:383.PubMedCrossRef

39.

Bai L, et al. Targeted degradation of BET proteins in triple-negative breast Cancer. Cancer Res. 2017;77:2476–87.PubMedPubMedCentralCrossRef

40.

Raina K, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016;113:7124–9.PubMedPubMedCentralCrossRef

41.

Remillard D, et al. Degradation of the BAF complex factor BRD9 by Heterobifunctional ligands. Angew Chem Int Ed Engl. 2017;56:5738–43.PubMedPubMedCentralCrossRef

42.

Zoppi V, et al. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel-Lindau (VHL) based dual degrader probe of BRD9 and BRD7. J Med Chem. 2019;62:699–726.PubMedCrossRef

43.

Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. 2014;13:337–56.PubMedCrossRef

44.

Ocana A, et al. BET inhibitors as novel therapeutic agents in breast cancer. Oncotarget. 2017;8:71285–91.PubMedPubMedCentralCrossRef

45.

Bian J, et al. Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity. Bioorg Chem. 2018;81:373–81.PubMedCrossRef

46.

Robb CM, et al. Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). Chem Commun Camb Engl. 2017;53:7577–80.CrossRef

47.

Jiang Y, et al. Development of stabilized peptide-based PROTACs against estrogen receptor alpha. ACS Chem Biol. 2018;13:628–35.PubMedCrossRef

48.

Papatzimas JW, et al. From inhibition to degradation: targeting the Antiapoptotic protein myeloid cell leukemia 1 (MCL1). J Med Chem. 2019;62:5522–40.PubMedCrossRef

49.

Farnaby W, et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019;15:672–80.PubMedPubMedCentralCrossRef

50.

Kong X, et al. Drug discovery targeting anaplastic lymphoma kinase (ALK). J Med Chem. 2019;62:10927–54.PubMedCrossRef

51.

Kang CH, et al. Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC). Biochem Biophys Res Commun. 2018;505:542–7.PubMedCrossRef

52.

McCoull W, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6. ACS Chem Biol. 2018;13:3131–41.PubMedCrossRef

53.

Khan S, et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47.PubMedPubMedCentralCrossRef

54.

Su S, et al. Potent and preferential degradation of CDK6 via proteolysis targeting chimera degraders. J Med Chem. 2019;62:7575–82.PubMedPubMedCentralCrossRef

55.

Brand M, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 2019;26:300–6 e9.PubMedCrossRef

56.

Liu L, et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinforma Oxf Engl. 2019;35:2882–4.CrossRef

57.

Zhang X, et al. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat Chem Biol. 2019;15:737–46.PubMedPubMedCentralCrossRef

58.

Hughes SJ, Ciulli A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays Biochem. 2017;61:505–16.PubMedPubMedCentralCrossRef

59.

Roy RD, et al. Cooperative binding mitigates the high-dose hook effect. BMC Syst Biol. 2017;11:74.PubMedPubMedCentralCrossRef

60.

Burslem GM, et al. The advantages of targeted protein degradation over inhibition: An RTK case study. Cell Chem. Biol. 2018;25:67–77 e3.PubMedCrossRef

61.

Olson CM, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat Chem Biol. 2018;14:163–70.PubMedCrossRef

62.

Testa A, et al. 3-Fluoro-4-hydroxyprolines: synthesis, conformational analysis, and Stereoselective recognition by the VHL E3 ubiquitin ligase for targeted protein degradation. J Am Chem Soc. 2018;140:9299–313.PubMedPubMedCentralCrossRef

63.

Chan K-H, et al. Impact of target warhead and linkage vector on inducing protein degradation: comparison of Bromodomain and extra-terminal (BET) degraders derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET inhibitor scaffolds. J Med Chem. 2018;61:504–13.PubMedCrossRef

64.

Smith BE, et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 2019;10:131.PubMedPubMedCentralCrossRef

65.

Cromm PM, et al. Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J Am Chem Soc. 2018;140:17019–26.PubMedCrossRef

66.

Bondeson DP, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 2018;25:78–87 e5.PubMedCrossRef

67.

Zeng M, et al. Exploring targeted degradation strategy for oncogenic KRAS(G12C). Cell Chem. Biol. 2020;27:19–31 e6.PubMedCrossRef

68.

Khongorzul P, et al. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res MCR. 2020;18:3–19.PubMedCrossRef

69.

Niza E, et al. Trastuzumab-targeted biodegradable nanoparticles for enhanced delivery of Dasatinib in HER2+ Metastasic breast Cancer. Nanomater. Basel Switz. 2019;9.

70.

Beck A, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37.PubMedCrossRef

71.

Pillow TH, et al. Antibody conjugation of a chimeric BET degrader enables in vivo activity. ChemMedChem. 2020;15:17–25.PubMedCrossRef

72.

Honigberg LA, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107:13075–80.PubMedPubMedCentralCrossRef

73.

Woyach JA, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.PubMedPubMedCentralCrossRef

74.

Pagliarini R, et al. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 2015;16:280–96.PubMedPubMedCentralCrossRef

75.

Tinworth CP, et al. PROTAC-mediated degradation of Bruton’s tyrosine kinase is inhibited by covalent binding. ACS Chem Biol. 2019;14:342–7.PubMedCrossRef

76.

Flanagan JJ, Qian Y, Gough SM. ARV-471, an oral estrogen receptor PROTAC™ protein degrader for breast cancer. SABCS. 2018;P5–04–18.

77.

Salami J, et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol. 2018;1:100.PubMedPubMedCentralCrossRef

78.

Zhang L, et al. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in Core components of E3 ligase complexes. Mol Cancer Ther. 2019;18:1302–11.PubMedCrossRef

79.

Ottis P, et al. Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem Biol. 2019;14:2215–23.PubMed

80.

Mayor-Ruiz C, et al. Plasticity of the Cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation. Mol. Cell. 2019;75:849–58 e8.PubMedCrossRef

81.

Silva MC, et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife. 2019;8:e45457.

82.

Nunes J, et al. Targeting IRAK4 for degradation with PROTACs. ACS Med Chem Lett. 2019;10:1081–5.PubMedPubMedCentralCrossRef

83.

Saenz DT, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31:1951–61.PubMedPubMedCentralCrossRef

84.

Tovell H, et al. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader. ACS Chem Biol. 2019;14:2024–34.PubMedPubMedCentralCrossRef

85.

Bai L, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511 e17.PubMedCrossRefPubMedCentral

86.

Vollmer S, et al. Design, synthesis, and biological evaluation of MEK PROTACs. J Med Chem. 2020;63:157–62.PubMedCrossRef

87.

Burslem GM, et al. Enhancing Antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J Am Chem Soc. 2018;140:16428–32.PubMedCrossRef

88.

Tovell H, et al. Rapid and reversible knockdown of endogenously tagged Endosomal proteins via an optimized HaloPROTAC degrader. ACS Chem Biol. 2019;14:882–92.PubMedPubMedCentralCrossRef

89.

Lai AC, et al. Modular PROTAC Design for the Degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed Engl. 2016;55:807–10.PubMedCrossRef

90.

Chen H, et al. Pomalidomide hybrids act as proteolysis targeting chimeras: synthesis, anticancer activity and B-Raf degradation. Bioorg Chem. 2019;87:191–9.PubMedCrossRef

91.

Li Y, et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J Med Chem. 2019;62:448–66.PubMedCrossRef

Title: Proteolysis targeting chimeras (PROTACs) in cancer therapy
Authors: Alberto Ocaña
Atanasio Pandiella
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-020-01672-1

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