Prof Guillaume Lessene, Division Head | WEHI Researcher Profile

Q: Developing small molecules that target Bcl-2 pro-survival proteins

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.

Q: Developing small molecules that inhibit apoptosis

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.

Q: Developing small molecule inhibitors of necroptosis

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.

Q: Targeting mRNA export to treat cancer

In collaboration with A/Prof Vi Wickramasinghe (Peter MacCallum Cancer Centre), a world leader in the study of RNA export processes (https://www.petermac.org/research/labs/vihandha-wickramasinghe), 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.

About

Our laboratory applies medicinal chemistry and chemical biology approaches to basic and translational research. We collaborate closely with researchers, both at the institute and externally, to undertake multidisciplinary research programs encompassing chemistry, structural biology, high throughput screening, biochemistry and biology.

A core research goal of our laboratory is to use small molecule probes to understand the key pathways—apoptosis and necroptosis—that govern whether a cell lives or dies. Cell survival or death is an important contributor to many diseases. Our research aims to novel therapies for cancers, inflammatory conditions, ischaemic brain injury and stroke.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof Guillaume Lessene

2025;

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

Emery‐Corbin SJ, Yousef JM, Adhikari S, Sumardy F, Nhu D, van Delft MF, Lessene G, Dziekan J, Webb AI, Dagley LF. Improved drug target deconvolution with PISA‐DIA using an extended, overlapping temperature gradient. Proteomics. 2024;24(16):10.1002/pmic.202300644

Wu X, Go M, Nguyen JV, Kuchel NW, Lu BGC, Zeglinski K, Lowes KN, Calleja DJ, Mitchell JP, Lessene G, Komander D, Call ME, Call MJ. Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape. Nature Communications. 2024;15(1):10.1038/s41467-024-50566-9

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

Chüeh AC, Tse JWT, Dickinson M, Ioannidis P, Jenkins L, Togel L, Tan B, Luk I, Davalos-Salas M, Nightingale R, Thompson MR, Williams BRG, Lessene G, Lee EF, Fairlie WD, Dhillon AS, Mariadason JM. Correction: ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors Across Tumor Types.Clinical Cancer Research. 2023;29(18):10.1158/1078-0432.ccr-23-2100

Davies K, Meng Y, Fitzgibbon C, Young S, Garnish S, Horne C, Luo C, Garnier J, Liang L, Cowan A, Samson A, Lessene G, Sandow J, Czabotar P, Murphy J. Dissecting the RIPK3/MLKL necroptotic molecular switch. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323087788

Pierotti CL, Jacobsen AV, Grohmann C, Dempsey RK, Etemadi N, Hildebrand JM, Fitzgibbon C, Young SN, Davies KA, Kersten WJA, Silke J, Lowes KN, Sabroux HJ, Huang DCS, van Delft MF, Murphy JM, Lessene G. The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase. Biochemical Journal. 2023;480(9):10.1042/bcj20230035

Wang Z, Hu H, Heitink L, Rogers K, You Y, Tan T, Suen CLW, Garnham A, Chen H, Lieschke E, Diepstraten ST, Chang C, Chen T, Moujalled D, Sutherland K, Lessene G, Sieber OM, Visvader J, Kelly GL, Strasser A. The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells. Cell Death & Differentiation. 2023;30(4):10.1038/s41418-023-01122-3