The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer
Open accessAbstract
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.
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Cites
Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K., & Jenuwein, T. (2001) · Nature · doi:10.1038/35065132 · Cited by 2,868
Cited by
IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis
Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.030 · Cited by 1,218
Small 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
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Arkin, M. R., Tang, Y., & Wells, J. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.001 · Cited by 1,065
Targeting IAP proteins for therapeutic intervention in cancer
Fulda, S., & Vucic, D. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3627 · Cited by 837
Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja209924v · Cited by 569
Metadata
- Authors
- Oost, T. K., Sun, C., Armstrong, R. C., Al-Assaad, A.-S., Betz, S. F., Deckwerth, T. L., Ding, H., Elmore, S. W., Meadows, R. P., Olejniczak, E. T., Oleksijew, A., Oltersdorf, T., Rosenberg, S. H., Shoemaker, A. R., Tomaselli, K. J., Zou, H., & Fesik, S. W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2004-07-31
- Volume
- 47
- Issue
- 18
- Pages
- 4417-4426
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1976353819
- Cited by
- 366
- References
- 1
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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