Targeting Cytotoxic Agents to Tumours through Small Molecule Covalent Binding
Lead Research Organisation:
Newcastle University
Department Name: School of Chemistry
Abstract
Overview
Abstract
The ability to target a potent cytotoxic agent selectively to a tumour is very attractive and has been a holy grail of cancer research for many years. We are developing methods that use covalent inhibitors as targeting agents to carry drug molecules to tumour cells. Once this occurs, a subsequent reaction will trigger release of a linked cytotoxic agent. Provided the protein target of the covalent inhibitor is overexpressed in tumour cell, the cytotoxic agent will be able to target these cells selectively. We anticipate that this will lead to improved cancer cell killing with the potential for reduced side effects.
In the project we will develop new release mechanisms, optimize these mechanisms using model systems and then assess the potential of the systems to exert selective anti-tumour effects in cellular experiments. These results will then be applied to the development a range of systems using different cytotoxic effects and targeting vehicles.
Impact
This work will explore a new method of selective delivery of molecules to tumour cells. We anticipate that insights gained from this will lead to new approaches to cancer therapy with potential advantages over existing protocols. The general principle will also be applicable to specific targeting of proteins in other disease areas and in chemical biology applications.
Abstract
The ability to target a potent cytotoxic agent selectively to a tumour is very attractive and has been a holy grail of cancer research for many years. We are developing methods that use covalent inhibitors as targeting agents to carry drug molecules to tumour cells. Once this occurs, a subsequent reaction will trigger release of a linked cytotoxic agent. Provided the protein target of the covalent inhibitor is overexpressed in tumour cell, the cytotoxic agent will be able to target these cells selectively. We anticipate that this will lead to improved cancer cell killing with the potential for reduced side effects.
In the project we will develop new release mechanisms, optimize these mechanisms using model systems and then assess the potential of the systems to exert selective anti-tumour effects in cellular experiments. These results will then be applied to the development a range of systems using different cytotoxic effects and targeting vehicles.
Impact
This work will explore a new method of selective delivery of molecules to tumour cells. We anticipate that insights gained from this will lead to new approaches to cancer therapy with potential advantages over existing protocols. The general principle will also be applicable to specific targeting of proteins in other disease areas and in chemical biology applications.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509528/1 | 01/10/2016 | 31/03/2022 | |||
| 1770103 | Studentship | EP/N509528/1 | 01/10/2016 | 30/12/2020 | Pasquale Morese |
| Description | Within the award so far we have synthesised compounds which have undergone biological evaluations to test the novel drug delivery system. So far we have discovered they have a good affinity for the target receptor over the wild-type protein, and have good cell growth inhibition properties. Mass spectroscopy analysis has revealed that these compounds are forming a covalent bond to the target protein but are not releasing the cytotoxic agent as intended. |
| Exploitation Route | Data collected so far would may encourage others to use the delivery system developed here to target other proteins or diseases that are currently targeted with covalent inhibitor drugs. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |