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Ricolinostat is not a highly selective HDAC6 inhibitor

Nature Cancer volume 4, pages 807–808 (2023)Cite this article

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Matters Arising to this article was published on 15 June 2023

The Original Article was published on 30 December 2022

arising from T. Z. Zeleke et al. Nature Cancer https://doi.org/10.1038/s43018-022-00489-5 (2023)

A study in Nature Cancer by Zeleke et al.1 described the results of a clinical trial using the putative histone deacetylase (HDAC)6 inhibitor ricolinostat. However, independent lines of genetic and biochemical evidence indicate that ricolinostat is not a selective HDAC6 inhibitor and that the anti-cancer activity of this compound is a result of its ability to inhibit targets other than HDAC6. Here, we wish to highlight several published findings that call the results of Zeleke et al.1 into question.

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References

  1. Zeleke, T. Z. et al. Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer. Nat. Cancer 4, 257–275 (2023).

  2. Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl. Med. 11, eaaw8412 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Depetter, Y. et al. Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models. Int. J. Cancer 145, 735–747 (2019).

  4. Winkler, R. et al. Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition. Oncogene 41, 4560–4572 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lechner, S. et al. Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target. Nat. Chem. Biol. 18, 812–820 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Heinzlmeir, S. et al. Chemoproteomics-aided medicinal chemistry for the discovery of EPHA2 inhibitors. ChemMedChem 12, 999–1011 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Broad Institute. HDAC6 DepMap Gene Summary (2021); https://depmap.org/portal/gene/HDAC6?tab=overview

  10. Cengiz Seval, G. & Beksac, M. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma. Expert Opin. Drug Saf. 18, 563–571 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Shah, R. R. Safety and tolerability of histone deacetylase (HDAC) inhibitors in oncology. Drug Saf. 42, 235–245 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Silva, J. et al. Reply to: Ricolinostat is not a highly selective HDAC6 inhibitor. Nat. Cancer https://doi.org/10.1038/s43018-023-00583-2 (2023).

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Author information

Authors and Affiliations

  1. Proteomics Core Facility, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece

    Guillaume Médard

  2. Yale University School of Medicine, New Haven, CT, USA

    Jason M. Sheltzer

Authors
  1. Guillaume Médard
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  2. Jason M. Sheltzer
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Contributions

J.M.S. and G.M. wrote and edited this text.

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Correspondence to Jason M. Sheltzer.

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Competing interests

J.M.S. has received consulting fees from Merck, Pfizer, Ono Pharmaceutical and Highside Capital Management; is a member of the advisory board of Tyra Biosciences, BioIO and the Chemical Probes Portal; and is a cofounder of Meliora Therapeutics. G.M. declares no competing interests.

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Médard, G., Sheltzer, J.M. Ricolinostat is not a highly selective HDAC6 inhibitor. Nat Cancer 4, 807–808 (2023). https://doi.org/10.1038/s43018-023-00582-3

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