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Molecules 2018, 23(8), 1958; https://doi.org/10.3390/molecules23081958

Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation

1
Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
2
Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Junji Iwahara
Received: 17 July 2018 / Revised: 1 August 2018 / Accepted: 1 August 2018 / Published: 6 August 2018
(This article belongs to the Special Issue Protein-DNA Interactions: From Biophysics to Genomics)
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Abstract

Chromatin regulation is a critical aspect of nuclear function. Recent advances have provided detailed information about dynamic three-dimensional organization of chromatin and its regulatory factors. Mechanisms crucial for normal nuclear function and epigenetic control include compartmentalization of biochemical reactions by liquid-phase separated condensates and signal-dependent regulation of protein stability. Synthetic control of these phenomena by small molecules provides deep insight into essential activities such as histone modification, BAF (SWI/SNF) and PBAF remodeling, Polycomb repression, enhancer looping by cohesin and CTCF, as well as many other processes that contribute to transcription. As a result, a complete understanding of the spatiotemporal mechanisms that underlie chromatin regulation increasingly requires the use of fast-acting drugs and chemical probes. Here, we provide a comprehensive review of next-generation chemical biology tools to interrogate the chromatin regulatory landscape, including selective PROTAC E3 ubiquitin ligase degraders, degrons, fluorescent ligands, dimerizers, inhibitors, and other drugs. These small molecules provide important insights into the mechanisms that govern gene regulation, DNA repair, development, and diseases like cancer. View Full-Text
Keywords: degron; PROTAC; VHL; cereblon; rapamycin; FRB; FKBP; Halo-tag; SNAP-tag; chemically induced proximity degron; PROTAC; VHL; cereblon; rapamycin; FRB; FKBP; Halo-tag; SNAP-tag; chemically induced proximity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Cermakova, K.; Hodges, H.C. Next-Generation Drugs and Probes for Chromatin Biology: From Targeted Protein Degradation to Phase Separation. Molecules 2018, 23, 1958.

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