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

  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},
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… 
Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review
This review covers research and patent literature of the last 15 years dealing with the discovery and development of inhibitors of the Bcl-2 protein family and the feasibility of disrupting protein–protein interactions between anti-apoptotic and pro-APoptotic proteins, members of the H2O family, using peptidomimetics and small-molecule inhibitors has been successfully established.
Inhibitors of the Bcl-2 Protein Family as Sensitizers to Anticancer Agents
This chapter reviews the exciting approaches currently being used to inhibit anti-apoptotic Bcl-2 family members, and the biologically active small molecules that have been discovered or designed to specifically target this important family of proteins.
Hematologic malignancies: newer strategies to counter the BCL-2 protein
By targeting the DNA directly, the DNAi technology promises to be more effective compared with other gene-interference strategies that target the RNA or protein but leaves the dysregulated DNA functional.
Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy
BCL-XL–selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax, and demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors.
The BCL-2 protein family, BH3-mimetics and cancer therapy
The role of the BCL-2 protein family in the development and treatment of cancer is discussed, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing thedevelopment and already recognised potential of theBH3-mimetic compounds.
Identification of a Novel Bcl-2 Inhibitor by Ligand-Based Screening and Investigation of Its Anti-cancer Effect on Human Breast Cancer Cells
A novel Bcl-2 inhibitor is identified by QSAR screening, which exerted significant cytotoxic activity in breast cancer cells through inducing mitochondria-mediated apoptosis.
Targeting Bcl-2 Family Proteins: What, Where, When?
Mechanisms of how the Bcl-2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl -2 family inhibitors as anticancer drugs are discussed.
A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.
A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (pac litaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines and potentiates the activity of paclitaxel in vivo.
Small Molecule Inhibitors of Bcl-2 Family Proteins for Pancreatic Cancer Therapy
This review examines the efficacy, potency, and function of several small molecule inhibitor drugs targeted to the Bcl-2 family of proteins and their preclinical progress against PC and also discusses the anti-cancer potential of newer class of B cl-2 drugs.


Promise and problems of Bcl-2 antisense therapy.
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.
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
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
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.
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
Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.