Chemical Biology &
Target-Based Drug Design
 

We aim to develop safe, targeted drugs for the treatment of aggressive childhood cancers.

Team Leader

What we do

The past 50 years of progress in therapy for childhood cancers has resulted in remarkable gains in survival. However, this has been at the cost of serious long-term morbidity and mortality among survivors. This is due to the toxic side effects of first-line treatments of childhood cancer, including chemotherapy and radiotherapy, which have not changed over the past decades. Thus, there is an unmet need for novel and more efficient approaches to improve clinical outcomes and to reduce the burden of treatment-associated side effects.

In this context, targeted therapy arises as a promising avenue to overcome the limitations and risks of common childhood cancer treatments. This type of therapy targets the proteins that control how cancer cells grow and spread, and is the foundation of precision medicine.

Despite holding great promise in treating paediatric cancers, there is still a lot to learn about targeted therapies, especially because most are developed for adult cancers and finding the right protein to target is an enormous challenge. Our Group is dedicated to meeting this challenge by creating new methods for finding relevant protein targets, and developing new drug treatments that are specifically targeted to childhood cancers and therefore not only effective but also safe for use in children.

We aim to apply data science, computational chemistry and chemical biology tools to streamline the drug discovery process, working closely with the Drug Discovery Centre and THerapeutic INnovations for Kids (THINK) to establish in silico (computer-based) drug design. This virtual screening facility will significantly reduce the time taken to develop promising drug candidates and progress these to clinical trial.

Research projects

Chemical Biology tools for RNA-binding proteins: targeting and inhibition

Contact: Dr Jean Bertoldo, jbertoldo@ccia.org.au 

RNA-binding proteins (RBPs) are directly involved in all aspects of the RNA life cycle and, as such, play a pivotal role in gene expression regulation and cancer. By forming ribonucleoprotein complexes, RBPs dictate the fate of RNAs, most importantly their translation or degradation. Despite significant advancements in methods for RBP biology investigation, our understanding of RNA-protein interactions remains poor.

The use of chemical probes (small molecules that bind to RBPs) can facilitate this endeavour by providing a tool for RBP function interrogation and targeted inhibition, especially if focused on covalent probes that irreversibly bind to RBPs, which are known to enhance selectivity. However, most available RBP-targeting small molecules lack selectivity and there are no covalent probes available.

This project aims to address these hurdles by leveraging cutting-edge chemical biology tools to develop selective covalent chemical probes for RBP biology interrogation, thus expanding our knowledge of this important and often neglected class of non-catalytic proteins in childhood cancer. In addition, this project will lay the foundations for the development of potent RBP inhibitors with long-term health benefits and wide-ranging applications.

Uncovering the druggable RNA-binding proteome of childhood cancers for target-based drug discovery

Contact: Dr Jean Bertoldo, jbertoldo@ccia.org.au

In childhood cancers such as neuroblastoma, RNA-binding proteins (RBPs) − including the insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) and the LIN-28 family (LIN28B) − promote the growth and spread of cancer cells by enhancing MYCN levels, through the disruption of onco-suppressor microRNAs such as the miRNA let-7 family. IGF2BP1 is also a marker of poor overall survival in high-risk neuroblastoma groups.

These examples highlight the potential of RBPs. However, their mostly intractable nature, the underexplored RBPome in childhood cancer, and the lack of selectivity of known inhibitors hinder a more complete understanding of these oncogenic drivers and their value as drug targets. There is an opportunity to develop an innovative strategy to target RBPs with unknown functions in childhood cancers. In this project, we will pioneer the integration of computational chemistry, data science and chemoproteomic tools to accelerate the discovery of potent and selective RBP inhibitors for the development of new targeted childhood cancer drugs.

Team

 

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