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Inhibition of the Oncogenic KDM4 Family of Histone Lysine Demethylases

Abstract

The human body is made up of over 35 trillion cells, each of which contains an identical copy or two copies of DNA. These cells, however, diverge functionally and morphologically from one another as they occupy specialized niches in various tissues and organs. For example, some cells produce antibodies to ward off invading microbes as part of the immune system, others contract in response to electrical stimuli as part of the cardiac ventricular walls, and yet others pump ions against a concentration gradient as part of the renal tubules. Such diversity in organization and function arising from a common genome requires differential regulation of gene expression in different cell types. This is achieved through epigenetic control of chromatin, which consists of chemical modifications that do not change the DNA code itself.

Each modification must be carefully placed at the right times and at the right locations in the genome in order to achieve a proper transcriptional outcome. Sets of proteins that enzymatically ‘write’ and ‘erase’ epigenetic modifications are tightly regulated to ensure the proper temporal and spatial distribution of each mark. When this system is perturbed, often by mutation in reader or writer proteins or by modulation of their expression, diseases such as cancer may occur.

We are particularly interested in a set of enzymes, the KDM4 family, which removes transcriptionally repressive methylation of histone H3 lysine 9. This family of demethylases is known to promote oncogenesis, likely through inappropriate activation of oncogenic transcription in the setting of KDM4 amplification and overexpression. In order to study the mechanism by which this family promotes oncogenesis and also to validate it as a therapeutic target in cancer we have developed a novel series of demethylase inhibitors using a combination of computational docking, synthetic chemistry, in vitro biochemistry and structural biology. These inhibitors display favorable potency and selectivity towards a subset of histone lysine demethylases, and we believe they will serve as the starting point for the development of chemical probes of the KDM4 family.

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