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VDAC2 ligands selectively and potently block BAK-mediated apoptosis to allow long-term clonogenic cell survival

ABSTRACT: This study aimed to characterise the protein that a novel compound binds to, thus promoting its ability to inhibit BAK apoptotic activity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Jarrod Sandow

LAB HEAD: Andrew Webb

PROVIDER: PXD013129 | Pride | 2019-10-11

REPOSITORIES: Pride

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A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.

van Delft Mark F MF Chappaz Stephane S Khakham Yelena Y Bui Chinh T CT Debrincat Marlyse A MA Lowes Kym N KN Brouwer Jason M JM Grohmann Christoph C Sharp Phillip P PP Dagley Laura F LF Li Lucy L McArthur Kate K Luo Meng-Xiao MX Chin Hui San HS Fairlie W Douglas WD Lee Erinna F EF Segal David D Duflocq Stephane S Lessene Romina R Bernard Sabrina S Peilleron Laure L Nguyen Thao T Miles Caroline C Wan Soo San SS Lane Rachael M RM Wardak Ahmad A Lackovic Kurt K Colman Peter M PM Sandow Jarrod J JJ Webb Andrew I AI Czabotar Peter E PE Dewson Grant G Watson Keith G KG Huang David C S DCS Lessene Guillaume G Kile Benjamin T BT

Nature chemical biology 20191007 11

Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their a ...[more]

PMID: 31591564

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