| Literature DB >> 31591564 |
David C S Huang1,2, Guillaume Lessene3,4,5, Benjamin T Kile2,6,7, Mark F van Delft8,9, Stephane Chappaz2,6,7, Yelena Khakham2,6, Chinh T Bui2,6, Marlyse A Debrincat1,2, Kym N Lowes2,6,10, Jason M Brouwer2,11, Christoph Grohmann2,6, Phillip P Sharp2,6, Laura F Dagley2,10, Lucy Li2,6, Kate McArthur2,6,7, Meng-Xiao Luo2,6, Hui San Chin1,2, W Douglas Fairlie2,11,12,13, Erinna F Lee2,11,12,13, David Segal1,2, Stephane Duflocq2,6, Romina Lessene2,6, Sabrina Bernard2,6, Laure Peilleron2,6, Thao Nguyen2,6, Caroline Miles2,10, Soo San Wan2,10, Rachael M Lane2,6,7, Ahmad Wardak2,11, Kurt Lackovic2,10, Peter M Colman2,11, Jarrod J Sandow2,10, Andrew I Webb2,10, Peter E Czabotar2,11, Grant Dewson2,14, Keith G Watson2,6.
Abstract
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 absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.Entities:
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Year: 2019 PMID： 31591564 DOI： 10.1038/s41589-019-0365-8
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040