An inhibitor of Bcl-2 family proteins induces regression of solid tumours
| Autor: | Shinichi Kitada, Jacqueline M. O'Connor, John C. Reed, Wendt Michael D, Andrew M. Petros, Alexander R. Shoemaker, Anatol Oleksijew, David J. Augeri, Craig B. Thompson, Kunzer Aaron R, Jürgen Dinges, Thomas L. Deckwerth, Stanley J. Korsmeyer, Saul H. Rosenberg, Stephen K. Tahir, Barbara A. Belli, Paul Nimmer, Baole Wang, Shi Chung Ng, Steven W. Elmore, Anthony Letai, Wang Shen, Haichao Zhang, Tilman Oltersdorf, Stephen W. Fesik, Milan Bruncko, David G. Nettesheim, Robert C. Armstrong, Michael J. Mitten, Kevin J. Tomaselli, Mary K. Joseph, Philip J. Hajduk, Chi Li |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Programmed cell death Magnetic Resonance Spectroscopy BH3 Mimetic ABT-737 Lymphoma Paclitaxel Antineoplastic Agents Apoptosis Piperazines Nitrophenols Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Cell Line Tumor Neoplasms Animals Humans Carcinoma Small Cell Sulfonamides Multidisciplinary Chemistry Biphenyl Compounds Bcl-2 family Cytochromes c Drug Synergism Cell cycle Mitochondria Survival Rate Disease Models Animal Proto-Oncogene Proteins c-bcl-2 Biochemistry Cancer research Bcl-2 Homologous Antagonist-Killer Protein Obatoclax |
| Zdroj: | Nature. 435:677-681 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) 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 therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice. |
| Databáze: | OpenAIRE |
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