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

Int J Cancer. 2011 Apr 1;128(7):1724-35. doi: 10.1002/ijc.25484. Epub 2010 May 25.


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 (K(i) = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acenaphthenes / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Cell Line, Tumor
  • Fluorescence Resonance Energy Transfer / methods
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Transplantation
  • Peptide Fragments / chemistry
  • Protein Conformation
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Pyrroles / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein / chemistry*
  • bcl-2-Associated X Protein / chemistry*


  • 8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile
  • Acenaphthenes
  • Antineoplastic Agents
  • Bax protein (53-86)
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein