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Drug Insight: histone deacetylase inhibitors—development of the new targeted anticancer agent suberoylanilide hydroxamic acid

Nature Clinical Practice Oncology volume 2, pages 150–157 (2005)Cite this article

Abstract

This review focuses on the discovery and development of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA). Post-translational modifications of the histones of chromatin are important factors in regulating gene expression—so-called epigenetic gene regulation. Acetylation and deacetylation of lysine residues in histone tails, controlled by the activities of HDACs and histone acetyltransferases, are among the most studied post-translational modification of histones. In addition to chromatin protein, transcription factors, cell-signaling regulatory proteins, and proteins regulating cell death are substrates of HDACs and may be altered in function by HDAC inhibitors. HDAC inhibitors have several remarkable aspects. For instance, despite HDACs being ubiquitously distributed through chromatin, SAHA selectively alters the transcription of relatively few genes, and normal cells are at least 10-fold more resistant than transformed cells to SAHA and related HDAC inhibitor-induced cell death. HDAC inhibitors represent a relatively new group of targeted anticancer compounds, which are showing significant promise as agents with activity against a broad spectrum of neoplasms, at doses that are well tolerated by cancer patients. SAHA is one of the HDAC inhibitors most advanced in development. It is in phase I and II clinical trials for patients with both hematologic and solid tumors.

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Figure 1: Interaction showing SAHA inhibition of HDAC.

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Acknowledgements

The studies reviewed in this chapter representing research in the authors' laboratories were supported, in part, by grants from: the National Cancer Institute (P30-CA-08748-40); Robert J and Helen C Kleberg Foundation; DeWitt Wallace Fund for the Memorial Sloan-Kettering Cancer Center; Susan and Jack Rudin Foundation; and The David H Koch Prostate Cancer Research Award.

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Authors and Affiliations

  1. President Emeritus and a Member of the Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Paul A Marks

  2. Member of the Division of Solid Tumor Oncology, Department of Medicine, and Department of Medicine, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY, USA

    William Kevin Kelly

Authors
  1. William Kevin Kelly
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  2. Paul A Marks
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Corresponding author

Correspondence to Paul A Marks.

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Competing interests

Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold patents on hydroxamic acid based polar compounds, including SAHA, which are exclusively licensed to Aton Pharma, Inc., a Biotechnology Company acquired by Merck, Inc. Paul A Marks was a founder of Aton and both institutions and the founder had an equity position in Aton Pharma, Inc. Paul A Marks is a scientific consultant to Merck.

Glossary

PML-RARα

A specific chromosomal translocation, t(15;17), results in the fusion of the promyelocytic leukemia gene (PML) and the retinoic acid receptor gene (RARα)

CBFA2T1

Core-binding factor 2 translocated to 1, also known as AML1/ETO

RUBINSTEIN–TAYBI SYNDROME

A rare genetic disorder that causes developmental abnormalities of many organs, caused by mutations in the gene encoding CREB binding protein (CBP)

CDKN1A

Gene encoding the cyclin-dependent kinase inhibitor-1A protein, which is an important inhibitor of cellular proliferation in response to DNA damage

TNFSF10

Tumor necrosis factor (ligand) superfamily member 10 (also known as TRAIL or APO-2L)

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Kelly, W., Marks, P. Drug Insight: histone deacetylase inhibitors—development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Rev Clin Oncol 2, 150–157 (2005). https://doi.org/10.1038/ncponc0106

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