Prof Peter Czabotar, Division Head | WEHI Researcher Profile

About

The main focus of our research is to understand the control of cell death at the molecular level and to design therapeutics to target these pathways in disease settings.

One of these cell death pathways is called apoptosis and is regulated by the Bcl-2 family of proteins. In the past we have focused on how “guardian” proteins from the family keep the cell alive. Using information gleaned from our atomic characterization of these proteins we have worked with medicinal chemist colleagues to develop compounds to kill cancerous cells. Such drugs, so called BH3 mimetics, are now in the clinic for the treatment of CLL and AML, with the potential for other compounds to target family members in other cancer settings.

More recently we have switched our focus to the executioner members of the Bcl-2 family that are responsible for telling the cell to die. Our studies have revealed how executioners are activated and transformed into the entities that kill the cell. We now aim to use that information to develop drugs that can keep cells alive in setting such as stroke or neurodegenerative disorders in which tissue damage occurs to excessive cell death.

We are also exploring how the protein MLKL regulates a different type of cell death called necroptosis. After a necroptotic stimuli, MLKL is activated and ruptures the cell’s membrane, resulting in the release of inflammatory signals. As such, drugs that target MLKL have the potential to be useful for the treatment of inflammatory diseases.

We use structural biology, in particular protein crystallography and CryoEM, supported by biochemical and biological analyses, to decipher these cell death pathways. These tools allow us to observe the atomic details of cell death proteins, providing key insights into how they function at the molecular level and informing the development of therapeutic compounds capable of modulating their activity.

We also use these techniques to study other proteins important to human health, including: DNA binding proteins that are potential cancer therapeutic targets, SARS-CoV-2 proteins important for viral replication, and malarial proteins involved in parasite invasion of red blood cells.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof Peter Czabotar

Croce CM, Vaux D, Strasser A, Opferman JT, Czabotar PE, Fesik SW. The BCL-2 protein family: from discovery to drug development. Cell Death & Differentiation. 2025;:10.1038/s41418-025-01481-z

M. Bader S, Calleja DJ, Devine SM, Kuchel NW, Lu BGC, Wu X, Birkinshaw RW, Bhandari R, Loi K, Volpe R, Khakham Y, Au AE, Blackmore TR, Mackiewicz L, Dayton M, Schaefer J, Scherer L, Stock AT, Cooney JP, Schoffer K, Maluenda A, Kleeman EA, Davidson KC, Allison CC, Ebert G, Chen G, Katneni K, Klemm TA, Nachbur U, Georgy SR, Czabotar PE, Hannan AJ, Putoczki TL, Tanzer M, Pellegrini M, Lechtenberg BC, Charman SA, Call MJ, Mitchell JP, Lowes KN, Lessene G, Doerflinger M, Komander D. A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID. Nature Communications. 2025;16(1):10.1038/s41467-025-57905-4

Li K, Yap YQ, Moujalled DM, Sumardy F, Khakham Y, Georgiou A, Jahja M, Lew TE, De Silva M, Luo M-X, Gong J-N, Yuan Z, Birkinshaw RW, Czabotar PE, Lowes K, Huang DCS, Kile BT, Wei AH, Dewson G, van Delft MF, Lessene G. Differential regulation of BAX and BAK apoptotic activity revealed by small molecules. Science Advances. 2025;11(10):10.1126/sciadv.adr8146

Hodder AN, Sleebs BE, Adams G, Rezazadeh S, Ngo A, Jarman K, Scally S, Czabotar P, Wang H, McCauley JA, Olsen DB, Cowman AF. Structure–activity analysis of imino‐pyrimidinone‐fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors. The FEBS Journal. 2025;:10.1111/febs.70038

Brown FC, Wang X, Birkinshaw R, Chua CC, Morley T, Kasapgil S, Pomilio G, Blombery P, Huang DCS, Czabotar P, Priore SF, Yang G, Carroll M, Wei AH, Perl AE. Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia. Blood Advances. 2025;9(1):10.1182/bloodadvances.2024014446

Cater RJ, Ryan RM, Oakhill JS, Czabotar P, Murphy JM, Call MJ. Structure, function, surf, repeat: A week at Lorne Proteins 2024. Structure. 2024;32(11):10.1016/j.str.2024.10.007

Davies KA, Czabotar PE, Murphy JM. Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis. Current Opinion in Structural Biology. 2024;88:10.1016/j.sbi.2024.102891

Miller MS, Cowan AD, Brouwer JM, Smyth ST, Peng L, Wardak AZ, Uren RT, Luo C, Roy MJ, Shah S, Tan Z, Reid GE, Colman PM, Czabotar PE. Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids. The FEBS Journal. 2024;291(11):10.1111/febs.17031

Subas Satish HP, Iyer S, Shi MX, Wong AW, Fischer KC, Wardak AZ, Lio D, Brouwer JM, Uren RT, Czabotar PE, Miller MS, Kluck RM. A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells. Cell Death & Differentiation. 2024;31(6):10.1038/s41418-024-01289-3

Yuan Z, van Delft MF, Li MX, Sumardy F, Smith BJ, Huang DCS, Lessene G, Khakam Y, Jin R, He S, Smith NA, Birkinshaw RW, Czabotar PE, Dewson G. Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis. PLOS Biology. 2024;22(5):10.1371/journal.pbio.3002617