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 (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.
Zhang
Zhichao
Z
School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China. zczhang@dlut.edu.cn
Song
Ting
T
Zhang
Tiantai
T
Gao
Jin
J
Wu
Guiye
G
An
Lijia
L
Du
Guanhua
G
D000073:Acenaphthenes / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry*; D051028:bcl-2-Associated X Protein / Q000737:chemistry*
C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D000970:Antineoplastic Agents; C474007:Bax protein (53-86); C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein