Many proteins have been implicated as key drivers of cancer progression but fall within the class of \u201cchallenging drug targets\u201d which hinders development of new therapeutics. Drug targets such as protein-protein interactions typically fall within this class as they often lack precise binding pockets suitable for drug targeting and often do not rely on active sites for function. Therefore, designing effective inhibitors for such targets is difficult.
An alternative approach is to degrade the target protein, rather than inhibit, which could overcome these limitations. PROTACs (PROteolysis TArgeting Chimeras) are an emerging drug modality which recruit both the target protein and an E3 ligase to engage the cells own ubiquitin proteosomal degradation system, tagging the cancer-implicated protein for degradation. PROTACs are well suited for targeting protein-protein interactions or other challenging drug targets as they do not rely on inhibiting active sites or protein function.
This medicinal chemistry project will explore targeted protein degradation against new cancer-related protein drug targets that currently lack effective inhibitors as a potential therapeutic strategy.<\/p>\n\n\n\n
Aim <\/p>\n\n\n\n
The overall aim of this project is to develop a suite of PROTAC molecules that degrade key proteins implicated in the progression of cancer. This project consists of three main aims, with opportunities to tailor the project to the candidates\u2019 interests for any or all of the aims:
Aim 1: Design and synthesis of a library of PROTAC molecules
Aim 2: Biological evaluation of PROTACs in biophysical and cell-based assays
Aim 3: Optimisation and development of potential lead compounds for cancer treatment<\/p>\n\n\n\n
Objectives <\/p>\n\n\n\n
Aim 1: Several inhibitors that bind key cancer implicated proteins have been discovered, however lack the potency required for a potential drug candidate. A library of PROTACs will be designed and synthesised to degrade the target proteins and potentially increase drug potency. Various libraries will be designed and synthesised.
Aim 2: The binding affinity of PROTACs will be tested (SPR, NMR, FP) and their ability to degrade the protein target evaluated in cancer cells by western blotting. Their biological activity will also be assessed in cancer cell lines as potential therapeutics.
Aim 3: Using SAR, PROTACs will be optimised with consideration for PK\/PD properties. Design and optimisation will be guided by computational modelling and rational design.<\/p>\n\n\n\n
Significance <\/p>\n\n\n\n
Many proteins have been identified as key players in cancer progression, however fall within the class of challenging drug targets due to lack of discernible binding pockets or active sites for inhibitors to bind, making drug design difficult. This project aims to develop a suite of PROTAC molecules capable of degrading specific cancer drug targets to overcome the limitations of inhibitors, towards developing potential drug candidates. These cancers currently lack targeted therapies and often have poor prognosis, highlighting a need to develop effective new therapeutics.<\/p>\n\n\n\n
Ideal Candidate <\/p>\n\n\n\n
We are looking for a PhD candidate with excellent attention to detail, problem-solving skills, and a desire to learn new skills with an interest in medicinal chemistry and interdisciplinary research. Candidates with prior experience in synthetic organic chemistry and\/or chemical biology are desired for this project. Additionally, the applicants should meet the eligibility criteria for entry into a PhD program at Curtin University.\u00a0<\/p>\n\n\n\n
This project is open to Domestic applicants only.\u00a0<\/p>\n\n\n\n
Scholarship <\/p>\n\n\n\n
If you are identified as the preferred candidate for this project, you may be considered for an RTP scholarship<\/a>. <\/p>\n\n\n\n Enquires and How to Apply <\/p>\n\n\n\n For enquires about this opportunity contact Dr Lisa Alcock at\u00a0Lisa.Alcock@curtin.edu.au<\/a><\/p>\n\n\n\n