Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

Bingshe Han, Dongkyoo Park, Rui Li, Maohua Xie, Taofeek K. Owonikoko, Guojing Zhang, Gabriel L. Sica, Chunyong Ding, Jia Zhou, Andrew T. Magis, Zhuo G. Chen, Dong M. Shin, Suresh S. Ramalingam, Fadlo R. Khuri, Walter J. Curran, Xingming Deng

Research output: Contribution to journalArticle

70 Scopus citations

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 invivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome.

Original languageEnglish (US)
Pages (from-to)852-863
Number of pages12
JournalCancer Cell
Volume27
Issue number6
DOIs
StatePublished - Jun 8 2015

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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    Han, B., Park, D., Li, R., Xie, M., Owonikoko, T. K., Zhang, G., Sica, G. L., Ding, C., Zhou, J., Magis, A. T., Chen, Z. G., Shin, D. M., Ramalingam, S. S., Khuri, F. R., Curran, W. J., & Deng, X. (2015). Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy. Cancer Cell, 27(6), 852-863. https://doi.org/10.1016/j.ccell.2015.04.010