| Literature DB >> 26004684 |
Bingshe Han1, Dongkyoo Park1, Rui Li1, Maohua Xie1, Taofeek K Owonikoko2, Guojing Zhang2, Gabriel L Sica3, Chunyong Ding4, Jia Zhou4, Andrew T Magis5, Zhuo G Chen2, Dong M Shin2, Suresh S Ramalingam2, Fadlo R Khuri2, Walter J Curran1, Xingming Deng6.
Abstract
The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome.Entities:
Mesh：
Substances：
Year: 2015 PMID： 26004684 PMCID： PMC4470473 DOI： 10.1016/j.ccell.2015.04.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743