Towards novel small molecule spigenetic inhibitors
Author(s)
Baud, Matthias Gérard Jacky
Type
Thesis
Abstract
Studies during the last decades have shown the cellular epigenetic machinery to be of major importance in the control of gene expression in living organisms. Misregulation of these mechanisms has been described in a variety of cancers, and small molecule inhibitors of enzymes involved in epigenetic gene regulation have emerged as promising agents for the development of new anticancer therapies.
Naturally isolated products continue to play a significant role in anticancer drug discovery. We are interested in the structural and biological properties of the natural product Psammaplin A. Recent studies highlighted its extreme potency against both Histone Deacetylases (HDACs) and DNA Methyltransferase 1 (DNMT1) enzymes, which both play a central role in the regulation of gene expression and tumour development. In enzyme-based assays, Psammaplin A displayed potent activity (IC50s) against an HDAC extract (4.2 nM) and Dnmt1 (18.6 nM). Subsequent studies have shown Psammaplin A to exhibit significant cytotoxicity against a number of cancer cell lines. In vivo, studies showed inhibition of tumour growth in the A549 lung xenograph mouse model while maintaining low toxicity.
The goal of our project is to establish a structure-activity relationship (SAR) of Psammaplin A, in order to understand the structural features responsible for such HDAC and DNMT inhibition and help us in the design of new generations of drug-like molecules for epigenetic anticancer therapies. An important number of Psammaplin A analogues could be obtained in few steps from versatile reagents. We will present our synthetic routes towards libraries of Psammaplin A analogues, results on their biological activity, and recent developments towards novel epigenetic modulators.
Based on our high interest in HDACs, results of a number of other novel and early stage projects aimed at dissecting the chemical biology of HDACs will be presented.
Naturally isolated products continue to play a significant role in anticancer drug discovery. We are interested in the structural and biological properties of the natural product Psammaplin A. Recent studies highlighted its extreme potency against both Histone Deacetylases (HDACs) and DNA Methyltransferase 1 (DNMT1) enzymes, which both play a central role in the regulation of gene expression and tumour development. In enzyme-based assays, Psammaplin A displayed potent activity (IC50s) against an HDAC extract (4.2 nM) and Dnmt1 (18.6 nM). Subsequent studies have shown Psammaplin A to exhibit significant cytotoxicity against a number of cancer cell lines. In vivo, studies showed inhibition of tumour growth in the A549 lung xenograph mouse model while maintaining low toxicity.
The goal of our project is to establish a structure-activity relationship (SAR) of Psammaplin A, in order to understand the structural features responsible for such HDAC and DNMT inhibition and help us in the design of new generations of drug-like molecules for epigenetic anticancer therapies. An important number of Psammaplin A analogues could be obtained in few steps from versatile reagents. We will present our synthetic routes towards libraries of Psammaplin A analogues, results on their biological activity, and recent developments towards novel epigenetic modulators.
Based on our high interest in HDACs, results of a number of other novel and early stage projects aimed at dissecting the chemical biology of HDACs will be presented.
Date Issued
2011-11
Date Awarded
2012-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Barrett, Anthony
Fuchter, Matthew
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)