Date of Award

4-30-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dr. Peng George Wang

Second Advisor

Dr. Maged Henary

Third Advisor

Dr. Gangli Wang

Abstract

This dissertation focuses on two aspects, targeted cancer therapy based on epigenetics and cancer diagnostics using DNA encoded glycan libraries. The first part addresses cancer therapy, wherein we discuss the discovery of a new class of G9a inhibitors and development of dual inhibitors targeting epigenetic enzymes G9a and Histone Deacetylases (HDAC). Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) marked by methyltransferase enzyme G9a and global de-acetylation on histone proteins by deacetylation enzyme HDAC typically associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Our structure-based virtual screening identified a series of compounds as potential inhibitors of G9a. Among these new class of G9a inhibitors, DCG066 was confirmed by in vitro biochemical, and cell-based enzyme assays. In another effort, several compounds featuring both G9a and HDAC pharmacophore was synthesized and screened for their dual activity and presented their detailed structure-activity relationship studies. Secondly, this dissertation elaborates a new method for the detection of cancer. Tumor-associated antigens like Globo H, are found in many cancers including breast cancer and ovarian cancer. Applying principles of DNA encoding and screening, we developed a DNA encoded glycan library (DEGL) of these tumor specific glycans. Then, DEGL is used to detect cancer by screening the serum samples for anti-Globo H antibodies.

DOI

https://doi.org/10.57709/11982327

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