A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1

Broad spectrum Bcl‐2 small molecule inhibitors act as BH3 mimetics are effective antitumor agents. Herein, we have identified S1, a previously discovered small molecule Bcl‐2 inhibitor, as the first authentic BH3 mimetic as well as a dual, nanomolar inhibitor of Bcl‐2 and Mcl‐1 (Ki = 310 nM and 58 n...

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Bibliographic Details
Published in:International journal of cancer 2011-04, Vol.128 (7), p.1724-1735
Main Authors: Zhang, Zhichao, Song, Ting, Zhang, Tiantai, Gao, Jin, Wu, Guiye, An, Lijia, Du, Guanhua
Format: Article
Language:English
Subjects:
Acenaphthenes - pharmacology
Animals
Antineoplastic Agents - pharmacology
Apoptosis
bcl-2 Homologous Antagonist-Killer Protein - chemistry
bcl-2-Associated X Protein - chemistry
Bcl‐2
BH3 mimetics
Biological and medical sciences
Cell Line, Tumor
Fluorescence Resonance Energy Transfer - methods
Humans
Mcl‐1
Medical sciences
Mice
Mice, Inbred BALB C
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Transplantation
pan‐Bcl‐2 inhibitor
Peptide Fragments - chemistry
Protein Conformation
Proto-Oncogene Proteins - chemistry
Proto-Oncogene Proteins c-bcl-2 - metabolism
Pyrroles - pharmacology
Tumors
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Summary:Broad spectrum Bcl‐2 small molecule inhibitors act as BH3 mimetics are effective antitumor agents. Herein, we have identified S1, a previously discovered small molecule Bcl‐2 inhibitor, as the first authentic BH3 mimetic as well as a dual, nanomolar inhibitor of Bcl‐2 and Mcl‐1 (Ki = 310 nM and 58 nM, respectively). The results of fluorescence polarization assays, coimmunoprecipitation, fluorescent resonance energy transfer, and shRNA indicated that S1 can disrupt Bcl‐2/Bax, Mcl‐1/Bak and Bcl‐2/Bim heterodimerization in multiple cell lines, activate Bax accompanied by its translocation to mitochondrial, activate caspase 3 completely dependent on Bax/Bak, and in turn induce a Bim‐independent apoptosis. Moreover, S1 could induce apoptosis on the primary acute lymphoblastic leukemia cells regardless of Mcl‐1 level. Mechanism‐based single agent antitumor activity in a mouse xenograft H22 (mouse liver carcinoma) model ascertain its therapeutic potential. S1 represents a novel chemical class of antitumor leads that function solely as BH3 mimetics and pan‐Bcl‐2 inhibitors. In the meanwhile, S1 could become a unique tool for interactions between Bcl‐2 family proteins.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.25484