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Review
. 2018 Aug 6;23(8):1958.
doi: 10.3390/molecules23081958.

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

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Free PMC article
Review

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

Katerina Cermakova et al. Molecules. .
Free PMC article

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.

Keywords: FKBP; FRB; Halo-tag; PROTAC; SNAP-tag; VHL; cereblon; chemically induced proximity; degron; rapamycin.

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The chemical biology toolkit for investigating chromatin. New developments in chemical biology have yielded powerful new molecules to probe chromatin structure and dynamics.
Figure 2
Figure 2
Small-molecule inhibitors of chromatin modifiers. (A) Drugs and chemical probes targeting writers of methyl, acetyl, and ubiquityl marks on histone tails; (B) Drugs and chemical probes targeting readers and erasers of these epigenetic marks.
Figure 3
Figure 3
Rapid targeted protein degradation with heterobifunctional small molecules. (A) Proteins of interest are linked to E3 ubiquitin ligases. The ensuing polyubiquitination induces rapid proteasomal degradation; (B) Example heterobifunctional PROTAC small molecules and comparison of the kinetics of targeted degradation relative to traditional Cre/Lox inactivation.
Figure 4
Figure 4
Genetically encoded fusion strategies for targeted protein degradation. A variety of fusion tags exist that are suitable for orthogonal targeted protein degradation strategies. These strategies require recombinant expression in experimental systems.
Figure 5
Figure 5
Heterobifunctional small molecules for chemically induced proximity. (A) Chemically induced dimerization of SNAP-tag and Halo-tag with HaXS8; (B) Antibody-based chemically induced dimerization with AbCID (ABT-737); (C) Light-induced dimerization of E. coli dihydrofolate reductase (DHFR) and Halo-tag with cTMP-Htag; (D) Chemically induced dimerization of FRB and FKBP with rapamycin.
Figure 6
Figure 6
Disruption of phase-separated nuclear condensates with 1,6-hexanediol (1,6-HD). A hallmark of phase-separated nuclear condensates is sensitivity to 1,6-HD. As illustrated in this cartoon model, condensates typically shrink and disappear within seconds to minutes upon incubation with 2–10% 1,6-HD. Withdrawal of 1,6-HD rapidly restores dynamic condensate structure in the nucleus (Nuc).
Figure 7
Figure 7
Fluorescent ligands for direct visualization of protein dynamics in native chromatin. Improved photostability of rhodamine-based dyes and conjugation with chloroalkane reagents has resulted in bright, photostable, cell-permeable fluorescent dyes compatible with the Halo-tag system.

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