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

被引:37
作者
Cermakova, Katerina [1 ,2 ]
Hodges, H. Courtney [1 ,2 ,3 ]
机构
[1] Baylor Coll Med, Dept Mol & Cellular Biol, Ctr Precis Environm Hlth, Houston, TX 77030 USA
[2] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA
[3] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 USA
来源
MOLECULES | 2018年 / 23卷 / 08期
关键词
degron; PROTAC; VHL; cereblon; rapamycin; FRB; FKBP; Halo-tag; SNAP-tag; chemically induced proximity; ESTROGEN-RECEPTOR DEGRADER; HISTONE DEACETYLASE INHIBITORS; REFRACTORY MULTIPLE-MYELOMA; DNA METHYLATION INHIBITOR; ARYL-HYDROCARBON RECEPTOR; SMALL-MOLECULE INHIBITORS; ANTITUMOR-ACTIVITY; CHEMICAL PROBE; IN-VIVO; TOPOISOMERASE-II;
D O I
10.3390/molecules23081958
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:26
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