Pioneering technique could unlock targeted treatments for cancer

Journal Reference:

  1. Joshua P. Smalley, India M. Baker, Wiktoria A. Pytel, Li-Ying Lin, Karen J. Bowman, John W. R. Schwabe, Shaun M. Cowley, James T. Hodgkinson. Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells. Journal of Medicinal Chemistry, 2022; DOI: 10.1021/acs.jmedchem.1c02179

Members of the Leicester Institute of Structural and Chemical Biology, based at the University of Leicester, used proteolysis targeting chimeras (PROTACs) as a ‘bridge’ to degrade proteins implicated in cancer.

Scientists can manipulate the effectiveness of treatments by making changes to elements of this PROTAC bridge.

This new study, published in the Journal of Medicinal Chemistry, describes how Leicester researchers applied a previously-described protein degradation technique known as PROTACs to degrade histone deacetylation enzymes (HDACs) in a more targeted way than ever before.

HDACs play an important role in gene regulation, in which genes are switched ‘on’ and ‘off’, and are associated with a range of diseases, including cancer as well as various neurodegenerative disorders including Alzheimer’s disease.

Using this pioneering technique to target specific structures within cancerous cells could increase the potency and selectivity of new and existing drugs, meaning patients would require lower systemic exposure to drug treatments leading to a reduction in harmful side-effects to patients.

The group have been granted a patent by the European Patent Office for the pioneering technique.

Dr James Hodgkinson is an Associate Professor in Organic Chemistry and Chemical Biology at the University of Leicester and one of the corresponding authors for the study. He said:

“We are really excited about what these new molecules are capable of in cancer cells and their potential future development into medicines.

“Our next steps will involve optimising their chemical structure and biological properties so that one day they could be used to improve the lives of cancer patients.”

John Schwabe is Professor of Structural Biology and Director of the Leicester Institute of Structural and Chemical Biology, and also a corresponding author on the study. Professor Schwabe added:

“The potential of using specific degraders of therapeutic targets is very powerful.

“This work has been the result of a productive three-way collaboration between chemists, biologists and biophysicists — an exciting combination to deliver interdisciplinary research.”

The Leicester Institute of Structural and Chemical Biology leads interdisciplinary research across 22 separate research groups at the University of Leicester.

Other work includes innovative research to create a potential vaccine against Alzheimer’s disease.

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Pioneering technique could unlock targeted treatments for cancer

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