The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL
Open accessAbstract
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.
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Cites
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The Bcl2 family: regulators of the cellular life-or-death switch
Cory, S., & Adams, J. M. (2002) · Nature Reviews Cancer · doi:10.1038/nrc883 · Cited by 4,032
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
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Self-citationApplication of a Theory of Enzyme Specificity to Protein Synthesis
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Structure of Bcl-x L -Bak Peptide Complex: Recognition Between Regulators of Apoptosis
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Self-citationX-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death
Muchmore, S. W., Sattler, M., Liang, H., Meadows, R. P., Harlan, J. E., Yoon, H. S., Nettesheim, D., Chang, B. S., Thompson, C. B., Wong, S.-L., et al. (1996) · Nature · doi:10.1038/381335a0 · Cited by 1,467
Self-citationMechanisms of caspase activation
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Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
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Cited by
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3048 · Cited by 3,058
Self-citationABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
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Self-citationSmall molecules, big targets: drug discovery faces the protein–protein interaction challenge
Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137
From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors
Ashkenazi, A., Fairbrother, W. J., Leverson, J. D., & Souers, A. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.253 · Cited by 903
Inhibition of α-helix-mediated protein–protein interactions using designed molecules
Azzarito, V., Long, K., Murphy, N. S., & Wilson, A. J. (2013) · Nature Chemistry · doi:10.1038/nchem.1568 · Cited by 727
Metadata
- Authors
- Bruncko, M., Oost, T. K., Belli, B. A., Ding, H., Joseph, M. K., Kunzer, A., Martineau, D., McClellan, W. J., Mitten, M., Ng, S.-C., Nimmer, P. M., Oltersdorf, T., Park, C.-M., Petros, A. M., Shoemaker, A. R., Song, X., Wang, X., Wendt, M. D., Zhang, H., Fesik, S. W., Rosenberg, S. H., & Elmore, S. W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2007-01-26
- Volume
- 50
- Issue
- 4
- Pages
- 641-662
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2158467294
- Cited by
- 304
- References
- 23
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
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- Bruncko, M., Oost, T. K., Belli, B. A., Ding, H., Joseph, M. K., Kunzer, A., Martineau, D., McClellan, W. J., Mitten, M., Ng, S.-C., Nimmer, P. M., Oltersdorf, T., Park, C.-M., Petros, A. M., Shoemaker, A. R., Song, X., Wang, X., Wendt, M. D., Zhang, H., . . . Elmore, S. W. (2007). Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm061152t
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
