Date of Award

Spring 1-1-2017

Document Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Xiang Wang

Second Advisor

Wei Zhang

Third Advisor

Tarek Sammakia

Abstract

Gene expression is guided by epigenetic regulation, which can turn genes on and off, allowing for varied cellular phenotypes. This is accomplished by adding or subtracting functional groups on the tails of proteins around which DNA coils. These changes are made by enzymes such as histone methyltransferases (HMTs) that add methyl groups to specific lysine residues found on histone tails or histone demethylases (HDMs) that remove them. The process of histone modification is necessary for cellular growth and differentiation, but irregular activity is associated with mental disabilities and diseases such as cancer. These ideas will be briefly discussed in a broad overview along with a review of the current state of research regarding histone lysine methylation and demethylation.

What follows is the discovery and enhancement of a JHDM1A inhibitor built on a novel triazospirocyclic scaffold. The lead compound, HTS12214, was discovered by high-throughput screening and a structure-activity relationship study was conducted aiming to improve the binding affinity toward JHDM1A. A series of 24 analogs was synthesized and their binding affinities were evaluated using a fluorescence polarization binding assay.

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