Developing PROTACs from chemical probes - applications in cancer research

Lead Research Organisation: University of Sussex
Department Name: Sch of Life Sciences

Abstract

This project aims to initiate PROTACs research designed to deliver modified chemical probes that can be used to interrogate the function of some of the most intractable targets in cancer biology. It will explore two main ideas: targeting the cancer super-controller, Myc using PROTACs, and investigating novel approaches to hybrid molecule and PROTAC generation using different E3 ligases. Bio-Techne provides both commercial and chemical expertise that will allow the novel PROTAC tools to be quickly disseminated throughout the research community.

The specific goals of this project are:
1) To make and investigate hybrids of ISOX DUAL and thalidomide analogues as new PROTACs. We will start by using Lenalidomide, which has a suitable amine linker.
i. A suitable strategy makes use of a linker on ISOX DUAL positioned ideally in a solvent exposed region so that the E3 ligase does not interfere with the former's BRD binding mode. A co-crystal structure (PDB: 4NR7) of CBP/SGC-CBP300 suggests two potential linker sites: the morpholino moiety, and the para-phenyl substituent (methoxy group in SGC-CBP300).

2) To investigate the effects of single and combination agents comprising ISOXDUAL and phthalimides, plus the hybrid versions in ten different myeloma cell lines, plus primary samples.
i. Assay of effects on cell proliferation, IL-6 secretion, and cell cycle progression by FACS
ii. Western blots for IRF4, MYC and cyclin D1 expression for the above.
iii. Access to mouse model xenografts for selected compounds
3) Performing structural studies of PROTAC ternary complexes in collaboration with Stefan Knapp (SGC Frankfurt)
4) To investigate the use of PCAF BRD binders for hybrid molecule and PROTAC generation.
5) To design and test robust chemical synthetic routes which can easily be scaled up for commercial synthesis; with particular attention being paid to the linker regionand a modular design for final PROTAC tool compounds.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509784/1 01/10/2016 30/09/2021
1955336 Studentship EP/N509784/1 21/09/2017 31/03/2021 Anthony Edmonds