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Small molecule targeting of chromatin writers in cancer

Abstract

More than a decade after the launch of DNA methyltransferase and histone deacetylase inhibitors for the treatment of cancer, 2020 heralded the approval of the first histone methyltransferase inhibitor, revitalizing the concept that targeted manipulation of the chromatin regulatory landscape can have profound therapeutic impact. Three chromatin regulatory pathways—DNA methylation, histone acetylation and methylation—are frequently implicated in human cancer but hundreds of potentially druggable mechanisms complicate identification of key targets for therapeutic intervention. In addition to human genetics and functional screening, chemical biology approaches have proven critical for the discovery of key nodes in these pathways and in an ever-increasing complexity of molecularly defined human cancer contexts. This review introduces small molecule targeting approaches, showcases chemical probes and drug candidates for epigenetic writer enzymes, illustrates molecular features that may represent epigenetic dependencies and suggests translational strategies to maximize their impact in cancer therapy.

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Fig. 1: Enzymes involved in three major chromatin regulatory pathways.
Fig. 2: Epigenetic reprogramming in cancer.
Fig. 3: DNMT inhibition for cancer therapy.
Fig. 4: Role of CREBBP/EP300 in regulating enhancer-driven transcription, and mechanism of HAT inhibition in silencing transcriptional networks.
Fig. 5: Cellular processes in which PRMTs play essential roles.
Fig. 6: Cancer contexts for the development of PRC2 inhibitors and drug discovery approaches to inactivate PRC2.

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We would like to credit K. Vicari for the figure artwork.

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Conery, A.R., Rocnik, J.L. & Trojer, P. Small molecule targeting of chromatin writers in cancer. Nat Chem Biol 18, 124–133 (2022). https://doi.org/10.1038/s41589-021-00920-5

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