Cancer epigenetics drug discovery and development: the challenge of hitting the mark
Robert M. Campbell, Peter J. Tummino
Robert M. Campbell, Peter J. Tummino
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(1):64-69. https://doi.org/10.1172/JCI71605.
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Review Series

Cancer epigenetics drug discovery and development: the challenge of hitting the mark

Abstract

Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved “first generation” of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area.

Authors

Robert M. Campbell, Peter J. Tummino

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Figure 1

Epigenetic inhibitor mechanisms of action.

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Epigenetic inhibitor mechanisms of action. (A) Model of EZH2 mechanism o...
(A) Model of EZH2 mechanism of action in EZH2-mutant DLBCL. PRC2 is a 5-protein complex consisting of EZH2 (the catalytic protein), EED, SUZ12, AEBP2, and RbAp48. EZH2 catalyzes methylation of H3K27 to a mono-, di-, and trimethylated state, and EZH2-activating mutations in DLBCL result in higher K27 trimethylation. An EZH2 inhibitor inhibits the catalytic activity of the enzyme and, combined with the catalytic activity of the H3K27 histone demethylases UTX and JMJD3, decreases methylation at H3K27. In some cells, this results in gene de-repression (increased gene expression). (B) Model of DOT1L mechanism of action in MLL-rearranged leukemias. MLL fusion proteins, including fusions with MLL-ENL, MLL-AF9, MLL-AF4, MLL-ELL, and MLL-AF10, recruit DOT1L, which catalyzes mono- and dimethylation of H3K79, an essential step in RNA Pol II–mediated transcriptional elongation. A DOT1L inhibitor inhibits H3K79 methylation, which inhibits MLL-fusion protein mediated transcription. Adapted from Haematologica (70). (C) Model of BET mechanism of action. Brd4 protein recruits positive transcription elongation factor b (P-TEFb), an essential step in RNA Pol II–mediated transcriptional elongation. A BET inhibitor blocks the binding of BRD4 to acetylated lysines on nucleosome histones, inhibiting RNA Pol II–mediated transcription. Adapted from F1000 Biology Reports (71). Ac, acetylated histone residue.