Abstract

Discovery and validation of small molecules interfering with the BCL-2 driven apoptotic pathway

Guillaume Lessene, Associate Professor, The Walter And Eliza Hall Institute of Medical Research

Apoptosis, or programmed cell death, is a highly conserved biological process required for the removal of unwanted, damaged or infected cells. The central regulators of apoptotic programmed cell death belong to the BCL-2 family of proteins. A delicate interplay between members of this family that promote cell survival (e.g. BCL-2, BCL-XL, MCL-1) and those that induce cell death (e.g. BIM, BAD, BAX, BAK) dictates whether a cell will live or die. Deregulation of apoptosis has been linked to life-threatening conditions such as cancer and auto-immune diseases (where down-regulation of apoptosis leads to abnormal survival of rogue cells), or ischemia-reperfusion injuries and neurodegeneration (where increased apoptosis leads to the premature death of normal cells). Because of its central role in the regulation of apoptosis, the BCL-2-family proteins represent highly attractive targets both for chemical biology studies and drug discovery. This presentation describes our approaches to developing selective modulators of apoptosis, including our screening strategy that lead to the identification of confirmed hits, and our medicinal chemistry efforts to obtain lead compounds. The validation of on-target activity will also be discussed, providing a strong validation of their specific mode of action in a cellular context. These new classes of compounds constitute invaluable assets to explore the impact of apoptosis modulation on various diseases.