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Selective targeting of MYC mRNA by stabilized antisense oligonucleotides

Oncogene volume 40, pages 6527–6539 (2021)Cite this article

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Abstract

MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5ʹ- and 3ʹ-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5ʹ Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.

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Fig. 1: Design and characterization of a library of MYC-targeting antisense oligonucleotides.
Fig. 2: MYCASOs decrease MYC protein expression in cancer cell lines.
Fig. 3: MYCASOs downregulate MYC expression through RNase H1-mediated cleavage of MYC mRNA.
Fig. 4: Phenotypic response to MYCASO treatment.
Fig. 5: Transcriptomic analysis of MYCASO-3 treated cells.
Fig. 6: In vivo effects of MYASO-3 in a MYC-induced model of hepatocellular carcinoma.

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References

  1. Kalkat M, Melo JD, Hickman KA, Lourenco C, Redel C, Resetca D, et al. MYC deregulation in primary human cancers. Genes-basel. 2017;8:151.

    Article  PubMed Central  Google Scholar 

  2. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010;463:899–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W, Ho Y, et al. Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc Natl Acad Sci. 2014;111:E4946–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res. 1986;47:189–234.

    Article  CAS  PubMed  Google Scholar 

  5. Croce CM, Nowell PC. Molecular genetics of human B cell neoplasia. Adv Immunol. 1986;38:245–74.

    Article  CAS  PubMed  Google Scholar 

  6. Cheng S-WG, Davies KP, Yung E, Beltran RJ, Yu J, Kalpana GV. c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nat Genet. 1999;22:102–5.

    Article  CAS  PubMed  Google Scholar 

  7. McMahon SB, Wood MA, Cole MD. The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol. 2000;20:556–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Csh Perspect Med. 2013;3:a014217.

    Google Scholar 

  9. Lin CY, Lovén J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 2012;151:56–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sabò A, Kress TR, Pelizzola M, Pretis S, de, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 2014;511:488–92.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Walz S, Lorenzin F, Morton J, Wiese KE, Eyss B, von, Herold S, et al. Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 2014;511:483–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell. 1999;4:199–207.

    Article  CAS  PubMed  Google Scholar 

  13. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, et al. Modelling Myc inhibition as a cancer therapy. Nature 2008;455:679–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koehler AN. A complex task? Direct modulation of transcription factors with small molecules. Curr Opin Chem Biol. 2010;14:331–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, et al. Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc Natl Acad Sci. 2002;99:3830–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Clausen DM, Guo J, Parise RA, Beumer JH, Egorin MJ, Lazo JS, et al. In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-G5, a novel small-molecule inhibitor of c-Myc/Max dimerization. J Pharm Exp Ther 2010;335:715–27.

    Article  CAS  Google Scholar 

  17. Kiessling A, Wiesinger R, Sperl B, Berg T. Selective inhibition of c‐Myc/Max dimerization by a Pyrazolo[1,5‐a]pyrimidine. Chemmedchem 2007;2:627–30.

    Article  CAS  PubMed  Google Scholar 

  18. Wang H, Hammoudeh DI, Follis AV, Reese BE, Lazo JS, Metallo SJ, et al. Improved low molecular weight Myc-Max inhibitors. Mol Cancer Ther. 2007;6:2399–408.

    Article  CAS  PubMed  Google Scholar 

  19. Wang H, Chauhan J, Hu A, Pendleton K, Yap JL, Sabato PE, et al. Disruption of Myc-Max heterodimerization with improved cell-penetrating analogs of the small molecule 10074-G5. Oncotarget 2013;4:936–47.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xu Y, Shi J, Yamamoto N, Moss JA, Vogt PK, Janda KD. A credit-card library approach for disrupting protein–protein interactions. Bioorgan Med Chem. 2006;14:2660–73.

    Article  CAS  Google Scholar 

  21. Beaulieu M-E, Jauset T, Massó-Vallés D, Martínez-Martín S, Rahl P, Maltais L, et al. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy. Sci Transl Med. 2019;11:eaar5012. Mar 20

    Article  PubMed  PubMed Central  Google Scholar 

  22. Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell. 2019;36:483–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Struntz NB, Chen A, Deutzmann A, Wilson RM, Stefan E, Evans HL, et al. Stabilization of the Max homodimer with a small molecule attenuates Myc-driven transcription. Cell Chem Biol. 2019;26;26:1 37.

  24. Heikkila R, Schwab G, Wickstrom E, Loke SL, Pluznik DH, Watt R, et al. A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1. Nature 1987;328:445–9.

    Article  CAS  PubMed  Google Scholar 

  25. Holt JT, Redner RL, Nienhuis AW. An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation. Mol Cell Biol. 1988;8:963–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wickstrom EL, Bacon TA, Gonzalez A, Freeman DL, Lyman GH, Wickstrom E. Human promyelocytic leukemia HL-60 cell proliferation and c-myc protein expression are inhibited by an antisense pentadecadeoxynucleotide targeted against c-myc mRNA. Proc Natl Acad Sci. 1988;85:1028–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Leonetti C, Agnano ID, Lozupone F, Valentini A, Geiser T, Zon G, et al. Antitumor effect of c-myc antisense phosphorothioate oligodeoxynucleotides on human melanoma cells in vitro and in mice. Jnci J Natl Cancer Inst 1996;88:419–29.

    Article  CAS  PubMed  Google Scholar 

  28. Mui B, Raney SG, Semple SC, Hope MJ. Immune stimulation by a CpG-containing oligodeoxynucleotide is enhanced when encapsulated and delivered in lipid particles. J Pharmacol Exp Therapeutics. 2001;3:1185–92. https://jpet.aspetjournals.org/content/298/3/1185.short

    Google Scholar 

  29. Chan JH, Lim S, Wong WF. Antisense oligonucleotides: from design to therapeutic application. Clin Exp Pharm P 2006;33:533–40.

    Article  CAS  Google Scholar 

  30. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017;35:238–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Koshkin AA, Singh SK, Nielsen P, Rajwanshi VK, Kumar R, Meldgaard M, et al. LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition. Tetrahedron 1998;54:3607–30.

    Article  CAS  Google Scholar 

  32. Singh SK, Koshkin AA, Wengel J, Nielsen P. LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem Commun. 1998;0:455–6.

    Article  CAS  Google Scholar 

  33. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharm. 2010;50:259–93.

    Article  CAS  Google Scholar 

  34. Wu H, Lima WF, Zhang H, Fan A, Sun H, Crooke ST. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J Biol Chem 2004;279:17181–9.

    Article  CAS  PubMed  Google Scholar 

  35. Koch T, Orum H Locked Nucleic Acid. In: Crooke ST, editor. Antisense Drug Technology [Internet]. Second. CRC Press; 2007. p. 519–64. Available from: https://www.routledge.com/Antisense-Drug-Technology-Principles-Strategies-and-Applications-Second/Crooke/p/book/9780849387968.

  36. Burgess TL, Fisher EF, Ross SL, Bready JV, Qian YX, Bayewitch LA, et al. The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism. Proc Natl Acad Sci. 1995;92:4051–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Coulis CM, Lee C, Nardone V, Prokipcak RD. Inhibition of c-myc expression in cells by targeting an RNA-protein interaction using antisense oligonucleotides. Mol Pharm. 2000;57:485–94.

    Article  CAS  Google Scholar 

  38. Zhang Y, Castaneda S, Dumble M, Wang M, Mileski M, Qu Z, et al. Reduced expression of the androgen receptor by third generation of antisense shows antitumor activity in models of prostate cancer. Mol Cancer Ther. 2011;10:2309–19.

    Article  CAS  PubMed  Google Scholar 

  39. Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, Martin BK, et al. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature 2013;500:207–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Crooke ST, Wang S, Vickers TA, Shen W, Liang X. Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol. 2017;35:230–7.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang Y, Qu Z, Kim S, Shi V, Liao B, Kraft P, et al. Down-modulation of cancer targets using locked nucleic acid (LNA)-based antisense oligonucleotides without transfection. Gene Ther. 2011;18:326–33.

    Article  CAS  PubMed  Google Scholar 

  42. Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci. 2000;97:228–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Palomero T, Barnes KC, Real PJ, Bender JLG, Sulis ML, Murty VV, et al. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to γ-secretase inhibitors. Leukemia 2006;20:1279–87.

    Article  CAS  PubMed  Google Scholar 

  44. Cowley GS, Weir BA, Vazquez F, Tamayo P, Scott JA, Rusin S, et al. Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies. Sci Data. 2014;1:140035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a cancer dependency Map. Cell 2017;170:564–76.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Castanotto D, Lin M, Kowolik C, Wang L, Ren X-Q, Soifer HS, et al. A cytoplasmic pathway for gapmer antisense oligonucleotide-mediated gene silencing in mammalian cells. Nucleic Acids Res. 2015;43:9350–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146:904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Claassen GF, Hann SR. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest. Proc Natl Acad Sci. 2000;97:9498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. P Natl Acad Sci USA 2005;102:15545–50.

    Article  CAS  Google Scholar 

  50. Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN, et al. Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci. 2000;97:3260–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schuhmacher M, Kohlhuber F, Hölzel M, Kaiser C, Burtscher H, Jarsch M, et al. The transcriptional program of a human B cell line in response to Myc. Nucleic Acids Res. 2001;29:397–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Browne EP, Wing B, Coleman D, Shenk T. Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: viral block to the accumulation of antiviral mRNAs. J Virol 2001;75:12319–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang W, Yang H, Kong X, Mohapatra S, Juan-Vergara HS, Hellermann G, et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med. 2005;11:56–62.

    Article  CAS  PubMed  Google Scholar 

  54. Chow EK, Fan L, Chen X, Bishop JM. Oncogene‐specific formation of chemoresistant murine hepatic cancer stem cells. Hepatology 2012;56:1331–41.

    Article  CAS  PubMed  Google Scholar 

  55. Chery J, Petri A, Wagschal A, Lim S-Y, Cunningham J, Vasudevan S, et al. Development of locked nucleic acid antisense oligonucleotides targeting ebola viral proteins and host factor Niemann-Pick C1. Nucleic Acid Ther. 2018;28:273–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Klar R, Michel S, Schell M, Hinterwimmer L, Zippelius A, Jaschinski F. A highly efficient modality to block the degradation of tryptophan for cancer immunotherapy: locked nucleic acid-modified antisense oligonucleotides to inhibit human indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase expression. Cancer Immunol Immunother. 2020;69:57–67.

    Article  CAS  PubMed  Google Scholar 

  57. Le BT, Adams AM, Fletcher S, Wilton SD, Veedu RN. Rational design of short locked nucleic acid-modified 2′-O-methyl antisense oligonucleotides for efficient exon-skipping in vitro. Mol Ther - Nucleic Acids. 2017;9:155–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ross SJ, Revenko AS, Hanson LL, Ellston R, Staniszewska A, Whalley N, et al. Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci Transl Med. 2017;9:eaal5253.

    Article  PubMed  Google Scholar 

  59. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;7:314ra185–314ra185.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Casey SC, Baylot V, Felsher DW. MYC: master regulator of immune privilege. Trends Immunol. 2017;38:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schlee M, Hölzel M, Bernard S, Mailhammer R, Schuhmacher M, Reschke J, et al. c‐MYC activation impairs the NF‐κB and the interferon response: implications for the pathogenesis of Burkitt’s lymphoma. Int J Cancer. 2007;120:1387–95.

    Article  CAS  PubMed  Google Scholar 

  62. Schlee M, Schuhmacher M, Hölzel M, Laux G, Bornkamm GW. c‐MYC impairs immunogenicity of humcan B Cells. Adv Cancer Res. 2007;97:167–88.

    Article  CAS  PubMed  Google Scholar 

  63. Mondala PK, Vora AA, Zhou T, Lazzari E, Ladel L, Luo X, et al. Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Cell Stem Cell. 2021;28:1–14.

    Article  Google Scholar 

  64. Iwamoto N, Butler DCD, Svrzikapa N, Mohapatra S, Zlatev I, Sah DWY, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017;35:845–51.

    Article  CAS  PubMed  Google Scholar 

  65. Parham JS, Goldberg AC. Mipomersen and its use in familial hypercholesterolemia. Expert Opin Pharmacother 2019;20:127–31.

    Article  CAS  PubMed  Google Scholar 

  66. Hoy SM. Nusinersen: first global approval. Drugs. 2017;77:473–79.

    Article  CAS  PubMed  Google Scholar 

  67. Dowling JJ. Eteplirsen therapy for Duchenne muscular dystrophy: skipping to the front of the line. Nat Rev Neuro. 2016;12:675–76.

    Article  CAS  Google Scholar 

  68. Shang R, Song X, Wang P, Zhou Y, Lu X, Wang J, et al. Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma. Gut. 2020;0:1–12. 1136/gutjnl-2020-320716

    Google Scholar 

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Acknowledgements

We thank M. Gabay and D. Felsher (Stanford University), S. He, T. Look, E. Dhimolea, C. Mitsiades, and members of the Lurie Family Imaging Center (Dana-Farber Cancer Institute) for assistance with animal studies. This work was supported by a US National Cancer Institute (NCI) Pathway to Independence Award (K99/R00CA190861) (C.J.O), and institutional funding from DFCI, MGH, and the Broad Institute (J.E.B, C.J.O, T.G.), and the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute (D.G.A.).

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Authors and Affiliations

  1. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Taylor Gill & Daniel G. Anderson

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

    Taylor Gill & James E. Bradner

  3. Broad Institute of MIT & Harvard, Cambridge, MA, 02142, USA

    Taylor Gill & Christopher J. Ott

  4. Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, CA, 94143, USA

    Haichuan Wang, Junyan Tao & Xin Chen

  5. ENZON Pharmaceuticals, Cranford, NJ, 07016, USA

    Raj Bandaru & Yixian Zhang

  6. Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Matthew Lawlor, Chenyue Lu, Linda T. Nieman, David T. Ting & Christopher J. Ott

  7. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA

    Daniel G. Anderson

  8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA

    Daniel G. Anderson

  9. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA

    Daniel G. Anderson

  10. Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    David T. Ting, James E. Bradner & Christopher J. Ott

  11. Novartis Institutes for BioMedical Research, Cambridge, MA, 02139, USA

    James E. Bradner

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Contributions

TG designed and performed experiments, analyzed data; HW, JT performed animal experiments; RB synthesized reagents; ML performed bioinformatics analysis; CL, LTN performed immunohistochemistry analysis; YZ, DGA, DTT, XC supervised and planned research; YZ, JEB, CJO conceptualized study, supervised and planned research. TG, JEB, CJO wrote the paper.

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Correspondence to James E. Bradner or Christopher J. Ott.

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Competing interests

CJO, RB, YZ, and JEB are listed as inventors in an issued patent related to the compounds described in this manuscript (WO2013123451A1). D.T.T. has received consulting fees from ROME Therapeutics, Foundation Medicine, Inc., NanoString Technologies, EMD Millipore Sigma, Pfizer, and Third Rock Ventures that are not related to this work. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. DTT receives research support from ACD-Biotechne, PureTech Health LLC, and Ribon Therapeutics, which was not used in this work. Dr. Ting’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. JEB is now an executive and shareholder of Novartis and has been a founder and shareholder of SHAPE (acquired by Medivir), Acetylon (acquired by Celgene), Tensha (acquired by Roche), Syros, Regenacy and C4 Therapeutics.

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Gill, T., Wang, H., Bandaru, R. et al. Selective targeting of MYC mRNA by stabilized antisense oligonucleotides. Oncogene 40, 6527–6539 (2021). https://doi.org/10.1038/s41388-021-02053-4

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