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

doi:10.1016/j.ccell.2015.04.010

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

Pharmacology & Toxicology

Research output: Contribution to journal › Article › peer-review

102 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 language	English (US)
Pages (from-to)	852-863
Number of pages	12
Journal	Cancer Cell
Volume	27
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2015.04.010
State	Published - Jun 8 2015

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2015.04.010

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title = "Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy",

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.",

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

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doi = "10.1016/j.ccell.2015.04.010",

language = "English (US)",

volume = "27",

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AU - Han, Bingshe

AU - Park, Dongkyoo

AU - Li, Rui

AU - Xie, Maohua

AU - Owonikoko, Taofeek K.

AU - Zhang, Guojing

AU - Sica, Gabriel L.

AU - Ding, Chunyong

AU - Zhou, Jia

AU - Magis, Andrew T.

AU - Chen, Zhuo G.

AU - Shin, Dong M.

AU - Ramalingam, Suresh S.

AU - Khuri, Fadlo R.

AU - Curran, Walter J.

AU - Deng, Xingming

PY - 2015/6/8

Y1 - 2015/6/8

N2 - 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.

AB - 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.

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JO - Cancer Cell

JF - Cancer Cell

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Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

Abstract

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