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Review
. 2020 Jun 18;78(6):1086-1095.
doi: 10.1016/j.molcel.2020.04.023. Epub 2020 May 13.

Using Chemical Epigenetics to Target Cancer

Virangika K Wimalasena  1 , Tingjian Wang  2 , Logan H Sigua  1 , Adam D Durbin  3 , Jun Qi  4
Affiliations
Review

Using Chemical Epigenetics to Target Cancer

Virangika K Wimalasena et al. Mol Cell. .

Abstract

Transcription is epigenetically regulated by the orchestrated function of chromatin-binding proteins that tightly control the expression of master transcription factors, effectors, and supportive housekeeping genes required for establishing and propagating the normal and malignant cell state. Rapid advances in chemical biology and functional genomics have facilitated exploration of targeting epigenetic proteins, yielding effective strategies to target transcription while reducing toxicities to untransformed cells. Here, we review recent developments in conventional active site and allosteric inhibitors, peptidomimetics, and novel proteolysis-targeted chimera (PROTAC) technology that have deepened our understanding of transcriptional processes and led to promising preclinical compounds for therapeutic translation, particularly in cancer.

Keywords: PROTAC; chromatin; degrader; epigenetics; inhibitor; peptidomimetic; transcription.

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Conflict of interest statement

Declaration of Interests J.Q. is scientific co-founder and consultant for Epiphanes and shareholder of Zentalis.

Figures

Figure 1.
Figure 1.. PROTACs bridge a target protein of interest and an E3 ligase complex to induce selective degradation.
By the PROTAC strategy, a chemical structure bridging a target protein of interest (red) and the substrate receptor of an E3 ubiquitin ligase containing complex (green) results in E2-dependent ubiquitination of the target protein. This leads to recruitment of the target protein to the proteasome and proteasomal degradation. Differences between CRBN and VHL-based PROTAC complexes are demonstrated.
Figure 2.
Figure 2.. Epigenetic proteins drive alterations that can be targeted using chemical inhibitors and degraders.
Demonstrated are common classes of histone readers, writers and erasers, as well as nucleosome remodeling complexes, and their different classes of inhibitors. MBT - malignant brain tumor; PWWP - Proline-Tryptophan-Tryptophan-Proline; PKMT - protein lysine methyltransferase; PRMT - protein arginine methyltransferase; BRD - bromodomain; HAT - histone acetyltransferase; HDM - histone demethylase; HDAC - histone eacetylase; * - bifunctional inhibitor.
See this image and copyright information in PMC

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