Drug Discovery Toward Antagonists of Methyl-Lysine Binding Proteins

Herold, J. Martin; Ingerman, Lindsey A.; Gao, Canzhu; Frye, Stephen V.

doi:10.2174/1875397301005010051

Cited by 31 publications

(24 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Progress on development of small molecule inhibitors targeted to Kme reader modules is still in its infancy (reviewed in Herold et al 2011a) and new approaches will need to be developed for further progress. In this regard, current drugs have rather broad specificity profiles, requiring the next-generation epigenetic drugs to target dysregulated processes with increased specificity.…”

Section: Chromatin-based Therapeutic Modalitiesmentioning

confidence: 99%

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

Patel

2016

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

SUMMARYThis article outlines the protein modules that target methylated lysine histone marks and 5mC DNA marks, and the molecular principles underlying recognition. The article focuses on the structural basis underlying readout of isolated marks by single reader molecules, as well as multivalent readout of multiple marks by linked reader cassettes at the histone tail and nucleosome level. Additional topics addressed include the role of histone mimics, cross talk between histone marks, technological developments at the genomewide level, advances using chemical biology approaches, the linkage between histone and DNA methylation, the role for regulatory lncRNAs, and the promise of chromatin-based therapeutic modalities.

show abstract

Section: Chromatin-based Therapeutic Modalitiesmentioning

confidence: 99%

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

Patel

2016

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

show abstract

“…To further increase the complexity, minor sequence variation despite the similar structural fold of PHD domains can result in different binding preferences (19). Because PHD family is one of the largest and most diverse of the methyl-lysine readers (46) remains to be seen. Only with answers to these questions can we fully evaluate the compounds that target PHD domains for therapeutic applications.…”

Section: Opportunities For Pharmacologic Intervene Of Nsd2mentioning

confidence: 99%

NSD2 Is Recruited through Its PHD Domain to Oncogenic Gene Loci to Drive Multiple Myeloma

Huang

Chuai

et al. 2013

Cancer Research

View full text Add to dashboard Cite

Histone lysine methyltransferase NSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myeloma due to the t(4;14) translocation associated with 15% to 20% of cases of this disease. NSD2 has been found to be involved in myelomagenesis, suggesting it may offer a novel therapeutic target. Here we show that NSD2 methyltransferase activity is crucial for clonogenicity, adherence, and proliferation of multiple myeloma cells on bone marrow stroma in vitro and that NSD2 is required for tumorigenesis of t(4;14)þ but not t(4;14)À multiple myeloma cells in vivo. The PHD domains in NSD2 were important for its cellular activity and biological function through recruiting NSD2 to its oncogenic target genes and driving their transcriptional activation. By strengthening its disease linkage and deepening insights into its mechanism of action, this study provides a strategy to therapeutically target NSD2 in multiple myeloma patients with a t(4;14) translocation. Cancer Res; 73(20); 6277-88. Ó2013 AACR.

show abstract

“…The methyl-lysine reader modules are principally made up of the 'Royal family', including MBT domain, Tudor domain, and Chromodomain proteins [154]. The Tudor domains (named for the Tudor gene in drosophila) have 60 amino acids arranged in 4-5 antiparallel β-sheets to form a barrel-like structure [155,156].…”

Section: Mbt Protein Inhibitorsmentioning

confidence: 99%

Targeting epigenetic regulations in cancer

Ning

Zhao

et al. 2016

ABBS

View full text Add to dashboard Cite

Epigenetic regulation of gene expression is a dynamic and reversible process with DNA methylation, histone modifications, and chromatin remodeling. Recently, groundbreaking studies have demonstrated the importance of DNA and chromatin regulatory proteins from different aspects, including stem cell, development, and tumor genesis. Abnormal epigenetic regulation is frequently associated with diseases and drugs targeting DNA methylation and histone acetylation have been approved for cancer therapy. Although the network of epigenetic regulation is more complex than people expect, new potential druggable chromatin-associated proteins are being discovered and tested for clinical application. Here we review the key proteins that mediate epigenetic regulations through DNA methylation, the acetylation and methylation of histones, and the reader proteins that bind to modified histones. We also discuss cancer associations and recent progress of pharmacological development of these proteins.

show abstract

Drug Discovery Toward Antagonists of Methyl-Lysine Binding Proteins

Cited by 31 publications

References 78 publications

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

NSD2 Is Recruited through Its PHD Domain to Oncogenic Gene Loci to Drive Multiple Myeloma

Targeting epigenetic regulations in cancer

Contact Info

Product

Resources

About