Abstract
Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.Graphical abstract is adapted with permission from Kymera Therapeutics; Figure 1 in Jarvis LM. Targeted protein degraders are redefining how small molecules look and act. C– 96(8) (2018) https://cen.acs.org/articles/96/i8/targeted-protein-degraders-are-redefining-how-small-molecules-look-and-act.html.
Papers of special note have been highlighted as : • of interest
References
- 1. . Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12, 237 (2012).
- 2. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer 101(1), 3–27 (2004).
- 3. . Targeting ubiquitination for cancer therapies. Future Med. Chem. 7(17), 2333–2350 (2015).
- 4. . Targeting autophagy to overcome drug resistance in cancer therapy. Future Med. Chem. 7(12), 1535–1542 (2015).
- 5. . Global cancer statistics. CA: A. Cancer J. Clin. 61(2), 69–90 (2011).
- 6. . Global cancer statistics. CA: A. Cancer J. Clin. 49(1), 33–64 (1999).
- 7. . Current chemotherapies for recurrent/metastatic head and neck cancer. Anticancer Drugs 22(7), 621–625 (2011).
- 8. . Drugging the ‘undruggable’ cancer targets. Nat. Rev. Cancer 17(8), 502–508 (2017).
- 9. . Drugging undruggable molecular cancer targets. Annu. Rev. Pharmacol. Toxicol. 56(1), 23–40 (2016).
- 10. . Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nat. Rev. Drug Discov. 3, 301 (2004).
- 11. . Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin. Ther. 32(3), 437–453 (2010).
- 12. Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene 538(2), 217–227 (2014).
- 13. . Small molecules and their role in effective preclinical target validation. Future Med. Chem. 9(14), 1579–1582 (2017).
- 14. . Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714 (2013).
- 15. Emerging drugs in refractory colorectal cancer. Future Med. Chem. 7(12), 1491–1501 (2015).
- 16. . Structure-based systems biology for analyzing off-target binding. Curr. Opin. Struc. Biol. 21(2), 189–199 (2011).
- 17. . Rational application of drug promiscuity in medicinal chemistry. Future Med. Chem. 10(15), 1835–1851 (2018).
- 18. . Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy. Eur. J. Med. Chem. 142, 393–415 (2017).
- 19. . Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147 (2005).
- 20. . Development trends for human monoclonal antibody therapeutics. Nat. Rev. Drug Discov. 9, 767 (2010).
- 21. . RNA interference. Nature 418(6894), 244–251 (2002).
- 22. . Revealing the world of RNA interference. Nature 431(7006), 338–342 (2004).
- 23. . Leveraging therapeutic potential of multi-targeted siRNA inhibitors. Future Med. Chem. 1(9), 1671–1681 (2009).
- 24. . The role of microRNAs in photodynamic therapy of cancer. Eur. J. Med. Chem. 142, 550–555 (2017).
- 25. . Biotin conjugated organic molecules and proteins for cancer therapy: a review. Eur. J. Med. Chem. 145, 206–223 (2018).
- 26. . Drug discovery in the ubiquitin–proteasome system. Nat. Rev. Drug Discov. 5, 596 (2006).
- 27. . Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258(13), 8206–8214 (1983).
- 28. . Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70(1), 503–533 (2001).
- 29. . Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine 36, 553–562 (2018).
- 30. . Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J. Med. Chem. 61(2), 444–452 (2018).
- 31. . The PROTAC technology in drug development. Cell Biochem. Funct. 37(1), 21–30 (2019).
- 32. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25(1), 78–87.e75 (2018).
- 33. . Small-molecule PROTACS: new approaches to protein degradation. Angew. Chem. Int. Edit. 55(6), 1966–1973 (2016).
- 34. . Proteolysis-targeting chimeras for targeting protein for degradation. Future Med. Chem. 11(7), 723–741 (2019).
- 35. . Cu-catalyzed click reaction in carbohydrate chemistry. Chem. Rev. 116(5), 3086–3240 (2016).
- 36. . Click chemistry assisted synthesis of novel aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their cytotoxicity and cancer cell cycle alterations. Bioorg. Chem. 88, 102967 (2019).
- 37. . The growing applications of click chemistry. Chem. Soc. Rev. 36(8), 1249–1262 (2007).
- 38. . Medicinal attributes of 1,2,3-triazoles: current developments. Bioorg. Chem. 71, 30–54 (2017).
- 39. New modalities for challenging targets in drug discovery. Angew. Chem. Int. Edit. 56(35), 10294–10323 (2017).
- 40. . PROTACs: an emerging targeting technique for protein degradation in drug discovery. BioEssays 40(4), e1700247 (2018).
- 41. . Proteolysis targeting chimera (PROTAC): a paradigm-shifting approach in small molecule drug discovery. Curr. Top. Med. Chem. 18(16), 1354–1356 (2018).
- 42. . PROteolysis TArgeting Chimeras (PROTACs) – past, present and future. Drug Discov. Today: Technol. 31(1), 15–27 (2019).
- 43. . Waste disposal—an attractive strategy for cancer therapy. Science 355(6330), 1163–1167 (2017). • The first peptide-based PROteolysis TArgeting Chimeras (PROTACs) were present in this paper.
- 44. . Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98(15), 8554–8559 (2001).
- 45. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics 2(12), 1350–1358 (2003). • The first cell-permeable PROTACs were reported in this paper.
- 46. . Degradation of target protein in living cells by small-molecule proteolysis inducer. Bioorg. Med. Chem. Lett. 14(3), 645–648 (2004).
- 47. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene 27, 7201 (2008).
- 48. Chemical genetic control of protein levels: selective in vivo targeted degradation. J. Am. Chem. Soc. 126(12), 3748–3754 (2004).
- 49. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611 (2015).
- 50. . Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angew. Chem. Int. Edit. 53(9), 2312–2330 (2014).
- 51. . Targeting the undruggable proteome: the small molecules of my dreams. Chem. Biol. 17(6), 551–555 (2010). • The first small-molecule PROTACs were present in this paper.
- 52. . Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg. Med. Chem. Lett. 18(22), 5904–5908 (2008).
- 53. . 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(16), 5820–5826 (2010).
- 54. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334(6054), 376–380 (2011).
- 55. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett. 585(8), 1147–1152 (2011).
- 56. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin–proteasome pathway. Cell Death Dis. 5, e1513 (2014).
- 57. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci. 104(11), 1492–1498 (2013).
- 58. Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. Bioorg. Med. Chem. Lett. 26(20), 4865–4869 (2016).
- 59. . Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10(8), 1770–1777 (2015).
- 60. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 113(26), 7124–7129 (2016). • The first administered PROTAC in a Phase I clinical trial is reported in this paper.
- 61. . Treatment of prostate cancers and Kennedy's disease by PROTAC-androgen receptor degradation. ACS Med. Chem. Lett. 10(5), 701–702 (2019).
- 62. Discovery of a small-molecule degrader of bromodomain and extra-terminal (BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J. Med. Chem. 61(2), 462–481 (2018). • The first in vivo PROTACs technology is reported in this paper.
- 63. . Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc. Natl Acad. Sci. USA 110(22), 8942–8947 (2013).
- 64. A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 5(1), 10 (2019).
- 65. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49 (2014).
- 66. Identification of a primary target of thalidomide teratogenicity. Science 327(5971), 1345–1350 (2010).
- 67. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348(6241), 1376–1381 (2015).
- 68. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22(6), 755–763 (2015). • The first in-cell click formed PROTACs are reported in this paper.
- 69. . Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Central Sci. 2(12), 927–934 (2016).
- 70. . The growing impact of click chemistry on drug discovery. Drug Discov. Today 8(24), 1128–1137 (2003).
- 71. . Imidazopyridine linked triazoles as tubulin inhibitors, effectively triggering apoptosis in lung cancer cell line. Bioorg. Chem. 80, 714–720 (2018).
- 72. . Mechanism of the ligand-free CuI-catalyzed azide–alkyne cycloaddition reaction. Angew. Chem. Int. Edit. 44(15), 2210–2215 (2005).
- 73. . Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions. Science 340(6131), 457–460 (2013).
- 74. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514 (2017). • The first comprehensive study on PROTACs with triazole linker was reported in this paper.
- 75. A “click chemistry platform” for the rapid synthesis of bispecific molecules for inducing protein degradation. J. Med. Chem. 61(2), 453–461 (2018).
- 76. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals). J. Med. Chem. 61(2), 482–491 (2018).
- 77. . Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673 (2014).
- 78. . HDAC as onco target: reviewing the synthetic approaches with SAR study of their inhibitors. Eur. J. Med. Chem. 158, 620–706 (2018).
- 79. . Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives. Future Med. Chem. 4(11), 1439–1460 (2012).
- 80. Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg. Med. Chem. Lett. 28(14), 2493–2497 (2018).
- 81. . Developing potent PROTACs tools for selective degradation of HDAC6 protein. Protein Cell
doi:10.1007/s13238-019-0613-4 (2019) (Epub ahead of print). - 82. . Targeting Bruton's tyrosine kinase in B cell malignancies. Nat. Rev. Cancer 14, 219 (2014).
- 83. The development of Bruton‘s tyrosine kinase (BTK) inhibitors from 2012 to 2017: a mini-review. Eur. J. Med. Chem. 151, 315–326 (2018).
- 84. . Strategies to overcome resistance mutations of Bruton‘s tyrosine kinase inhibitor ibrutinib. Future Med. Chem. 10(3), 343–356 (2018).
- 85. . B-cell receptor pathobiology and targeting in NHL. Curr. Oncol. Rep. 14(5), 411–418 (2012).
- 86. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 28(7), 779–781 (2018).
- 87. Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia 33(8), 2105–2110 (2019).
- 88. PROTAC-mediated degradation of Bruton's tyrosine kinase is inhibited by covalent binding. ACS Chem. Biol. 14(3), 342–347 (2019).
- 89. Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity. Bioorg. Chem. 81, 373–381 (2018).
- 90. . PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer. Chem. Commun. 55(18), 2704–2707 (2019).
- 91. . Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20, 3247 (2001).
- 92. . Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. Science 267(5199), 894–897 (1995).
- 93. . Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway. Bioorganic Chem. 81, 536–544 (2018).
- 94. . Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule. Chem. Commun. 55(3), 369–372 (2019).
- 95. . Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discov. 4, 421 (2005).
- 96. . Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - a recent update. Eur. J. Med. Chem. 165, 198–215 (2019).
- 97. . A comprehensive look of poly(ADP-ribose) polymerase inhibition strategies and future directions for cancer therapy. Future Med. Chem. 9(1), 37–60 (2017).
- 98. . Greasy tags for protein removal. Nature 487, 308 (2012).
- 99. . Poloxin-2HT+: changing the hydrophobic tag of Poloxin-2HT increases Plk1 degradation and apoptosis induction in tumor cells. Org. Biomol. Chem. 17(12), 3113–3117 (2019).
- 100. Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay. Sci. Rep. 6, 37581 (2016).
- 101. Optimized Plk1 PBD inhibitors based on poloxin induce mitotic arrest and apoptosis in tumor cells. ACS Chem. Biol. 10(11), 2570–2579 (2015).