An inhibitor of Bcl-2 family proteins induces regression of solid tumours

@article{Oltersdorf2005AnIO,
  title={An inhibitor of Bcl-2 family proteins induces regression of solid tumours},
  author={Tilman Oltersdorf and Steven W. Elmore and Alexander R. Shoemaker and Robert C. Armstrong and David J. Augeri and Barbara A. Belli and Milan Bruncko and Thomas L. Deckwerth and Jurgen Dinges and Philip J. Hajduk and Mary K. Joseph and Shin-ichi Kitada and Stanley J. Korsmeyer and Aaron R. Kunzer and Anthony G. Letai and Chi Li and Michael J. Mitten and David G. Nettesheim and Shi Chung Ng and Paul M Nimmer and J. M. O'Connor and Anatol Oleksijew and Andrew M. Petros and John Calvin Reed and Wang Shen and Stephen K. Tahir and Craig B. Thompson and Kevin J. Tomaselli and Baole Wang and Michael D. Wendt and Haichao Zhang and Stephen W. Fesik and Saul H. Rosenberg},
  journal={Nature},
  year={2005},
  volume={435},
  pages={677-681}
}
Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-XL and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-XL expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer… 
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References

SHOWING 1-10 OF 33 REFERENCES
Promise and problems of Bcl-2 antisense therapy.
TLDR
Elevated expression of Bcl-2 can be associated with shorter survival and other indicators of worse clinical outcome in patients with at least some types of cancer, including aggressive non-Hodgkin’s lymphomas, acute myelogenous leukemias, and adenocarcinomas of the prostate.
Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening.
TLDR
It was found that compound 6 can be used as a valuable pharmacological tool to elucidate the function of Bcl-2 and also serves as a novel lead compound for further design and optimization of small-molecule inhibitors targeted at the BH3 binding pocket in B cl-2.
Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.
  • J. L. WangD. Liu Z. Huang
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2000
TLDR
The discovery of HA14-1, a small molecule and nonpeptidic ligand of a Bcl-2 surface pocket, provides a chemical probe to study B cl-2-regulated apoptotic pathways in vivo and could lead to the development of new therapeutic agents.
Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3
TLDR
It is demonstrated that antimycin A and a Bak BH3 peptide bind competitively to recombinant Bcl-2, demonstrating that a small non-peptide ligand can directly inhibit the function of B cl-2-related proteins.
Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment.
TLDR
A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors.
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
TLDR
Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.
...
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