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Structure-Based Design and Developme...

Smith, Steven G.

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Structure-Based Design and Development of Small Molecule Modulators of the CBX7 Chromodomain.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structure-Based Design and Development of Small Molecule Modulators of the CBX7 Chromodomain./
Author:	Smith, Steven G.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	142 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.
Contained By:	Dissertation Abstracts International78-07B(E).
Subject:	Molecular chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10257165
ISBN:	9781369571677

Structure-Based Design and Development of Small Molecule Modulators of the CBX7 Chromodomain.
Smith, Steven G.

Structure-Based Design and Development of Small Molecule Modulators of the CBX7 Chromodomain. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 142 p.

Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2017.

Epigenetic writers, erasers, and readers make up a suite of proteins responsible for the modulation of gene transcription in the context of chromatin. The plethora of post-translational modifications (PTMs) that can be placed, removed, or recognized on histone tails provide different signals within the cell that alter gene expression without changing the underlying DNA sequence. Altered gene expression due to the dysregulation of these PTMs and the proteins that govern them is a common hallmark in various diseases, including numerous types of cancer. This thesis covers the discovery and development of two classes of small molecule modulators of an epigenetic reader domain, the chromodomain (ChD) of chromobox homolog 7 (CBX7), which is responsible for recognizing methylated lysine residues on histones. Members of the first class of compounds, led by the parent compound MS452 and the top-performing optimized compound MS0521, inhibit methyl-lysine recognition by occupying the peptide-binding groove of the CBX7 ChD, while members of the second class of compounds, including the parent compound MS351, is located squarely within the aromatic cage region of the CBX7 ChD, and has the unique ability to bind through the formation of a ternary complex with the protein and a strand of long noncoding RNA. While MS452-family compounds showed great promise in vitro, only MS351-family compounds have shown appreciable cellular efficacy. These small molecules serve as important probes that enable the in-depth study of the CBX7 ChD and the many proteins it associates with in the cell, and importantly, have the potential to be developed into novel therapeutics that can treat multiple varieties of cancer, including prostate cancer.

ISBN: 9781369571677Subjects--Topical Terms:

1071612
Molecular chemistry.

Structure-Based Design and Development of Small Molecule Modulators of the CBX7 Chromodomain.
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