My research group, bringing together medicinal chemists and chemical biologists, aims at developing small molecules that:
We are particularly interested in cellular pathways controlling cell death, which are corrupted in many diseases, including cancers and inflammatory conditions. Our approaches combines medicinal chemistry, structure based-drug design and cutting edge small molecule target identification approaches.
We are a highly multidisciplinary team and we collaborate with many colleagues across WEHI and beyond.
Vision: First-in-class medicines and discovery biology through chemistry
Purpose: To work as a multidisciplinary team that leverage medicinal chemistry and chemical biology to make discoveries and develop novel medicines.
My lab is recognised for the development and biological characterisation of of small molecules targeting the BCL-2 family of proteins, essential regulators of a cell death process called apoptosis which is deregulated in all cancers. In collaboration with structural biology colleagues, we use use structure-based drug design and medicinal chemistry to design novel anti-cancer medicines.
More recently we leveraged chemical biology approaches, such as chemical probe design and chemoproteomics, to discover small molecules that block, rather than induce, apoptosis and highlighted the role of a mitochondrial protein called VDCA2 in regulating this process.
We are also investigating a more recently discovered cell death pathway called necroptosis and developing novel inhibitors of this inflammatory form of cell death for the treatments of conditions such as ischemia reperfusion injuries or inflammatory conditions.
Through structure-based drug design of peptide-mimetic scaffolds, we develop small molecules that target protein-protein interactions. Specifically, our team is interested in developing compounds that interfere with binding between proteins of the BCL-2 family. Our targets of interest within this family are BCL-XL and MCL1. We are particularly interested in increasing the therapeutic window of these agents (by enhancing their ability to target cancer cells), which can be used for anti-cancer treatments.
Team members: Duong Nhu, Fransisca Sumardy, Sophie Stevens.
Together with Professors Peter Czabotar and Grant Dewson, and Dr Mark van Delft, we aim to identify small molecules that inhibit apoptosis. We develop phenotypic and biochemical screens to discover potent and specific inhibitors of mitochondrial apoptosis. The unique chemical probes identified within these projects enable the investigations into the regulation of the pro-apoptotic proteins BAX and BAK and the assessment of apoptosis inhibition in models of diseases where excessive apoptosis has been implicated.
Team members: Yelena Khakham, Fransisca Sumardy, Romina Lessene.
In collaboration with institute colleagues including Profs James Murphy John Silke and Peter Czabotar, we are developing a range of chemical probes that modulate necroptosis, a programmed form of cellular necrosis. As most of the intricacies of this pathway are still unknown, we aim to use our chemical probes to identify new protein components of this pathway, and to employ the most advanced compounds to validate necroptosis inhibition in inflammatory diseases.
Team members: Chris Gardner, Jiahui Tng, Ying Zhang.
In collaboration with Assoc Prof Vi Wickramasinghe (Peter MacCallum Cancer Centre), a world leader in the study of RNA export processes, we are developing small molecules that may have applications in the treatment of cancer.
This project, using phenotypic and biochemical screening approaches to discover starting points, combines medicinal chemistry and chemical biology.
Team member: Yu Qing Yap
Chemistry is an essential component of successful biomedical research. With a strong focus on medicinal chemistry and chemical biology, our lab strives to integrate multi-disciplinary approaches based on cohesive teams of researchers.
To achieve this goal, we have strong collaborations with a number of WEHI labs and divisions and all our projects are run as a multidisciplinary, collegial teams.
We collaborate with the following laboratories at WEHI: