Invited Speaker Presentation 29th Lorne Cancer Conference 2017

Targeting BCL-2 family proteins to treat cancer: expanding the repertoire of small molecules BH3-mimetics  (#2)

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

Apoptosis, or programmed cell death, is a highly conserved biological process required for the removal of unwanted, damaged or infected cells1. The BCL-2 family of proteins governs the intrinsic apoptosis cascade. A delicate interplay between members of this family that promote cell survival (e.g. BCL-2, BCL-XL, MCL1) and those that induce cell death (e.g. “sensors” BIM or BAD and “executioners” BAX, BAK) dictates whether a cell will live or die.

Down-regulation of apoptosis, often through over-expression of pro-survival BCL-2 proteins is a hallmark of most if not all cancers. Due to their key role in the initiation and maintenance of tumours, the BCL-2-family proteins have become attractive, yet challenging, targets for drug discovery2.

BH3-mimetics, small molecules targeting the pro-survival BCL-2 proteins, are a new class of drugs that functionally replicate the tumour suppressor activity of sensor proteins such as BIM or BID 2. This presentation will highlight our decade-long efforts towards the discovery and characterisation of such agents focusing on the most recent developments targeting MCL13. From design to application in models of cancers, this work highlights the breakthrough that these compounds may represent in the fight against cancer.

  1. 1. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15: 49-63.
  2. 2. Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 2008; 7: 989-1000.
  3. 3. Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 2016; 538: 477-482