Oral Presentation Royal Australian Chemical Institute National Congress 2026

Targeting Cell Death Pathways: From Fundamental Biology to First-in-Class Therapeutics (137006)

Guillaume Lessene 1
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

Cell death processes are critical to embryonic development and the maintenance of homeostasis in mature organisms[1]. As a result, their deregulation underpins all major disease classes, from cancer and inflammatory disorders to from acute ischemic perfusion injuries to neurodegeneration. The ability to pharmacologically modulate cell death presents powerful opportunities to target fundamental cellular mechanisms and enable transformative therapeutic approaches.

Our team has long been engaged in the development of well-validated chemical probes and drug-like molecules targeting two major cell death pathways: apoptosis and necroptosis[2, 3].

Apoptosis, particularly the intrinsic pathway, is a largely silent, non-inflammatory form of cell death governed by the BCL-2 family of proteins[4]. Decades of foundational research have defined the critical interactions between pro-survival and pro-death members of this family and revealed opportunities for therapeutic intervention. Amongst these, the executioner proteins BAX and BAK remain a “holy grail” of drug discovery, offering the potential for both activation and inhibition of cell death[5, 6].

In contrast, necroptosis is a lytic pathway that results in membrane rupture and the release of highly inflammatory mediators[7]. Increasingly implicated across a broad spectrum of diseases, this pathway presents compelling opportunities for therapeutic modulation. Targeting key effectors such as RIPK1, RIPK3 or MLKL holds promise for novel, broadly applicable anti-inflammatory strategies[2].

In this presentation, I will describe our efforts to therapeutically target these pathways, using both activators and inhibitors, spanning the chemical biology-drug discovery continuum. These examples illustrate how advances in fundamental biology can drive first-in-class therapeutics, and how translational challenges, in turn, refine biological understanding. More broadly, the talk will highlight WEHI’s drug discovery strategy and the power of multidisciplinary teams tackling complex biomedical challenges.

  1. Aufschnaiter A, Oh TJ, Oberst A. The landscape of regulated cell death: It's all downhill from here. Mol Cell 2025.
  2. Gardner CR, Davies KA, Zhang Y, Brzozowski M, Czabotar PE, Murphy JM et al. From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors. J Med Chem 2023; 66: 2361-2385.
  3. Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 2008; 7: 989-1000.
  4. Diepstraten ST, Anderson MA, Czabotar PE, Lessene G, Strasser A, Kelly GL. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat Rev Cancer 2022; 22: 45-64.
  5. Li K, van Delft MF, Dewson G. Too much death can kill you: inhibiting intrinsic apoptosis to treat disease. EMBO J 2021; 40: e107341.
  6. Li K, Yap YQ, Moujalled DM, Sumardy F, Khakham Y, Georgiou A et al. Differential regulation of BAX and BAK apoptotic activity revealed by small molecules. Sci Adv 2025; 11: eadr8146.
  7. Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol 2017; 18: 127-136.