The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Open accessAbstract
The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and PI3-Ks, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography, and kinome-level biochemical profiling, we identify compounds that inhibit a spectrum of novel target combinations in these two families. Crystal structures reveal that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and PI3-Ks. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.
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Cites
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Cited by
Targeting the phosphoinositide 3-kinase pathway in cancer
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Combinatorial drug therapy for cancer in the post-genomic era
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Polypharmacology: Challenges and Opportunities in Drug Discovery: Miniperspective
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Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000038 · Cited by 1,082
Self-citation
Metadata
- Authors
- Apsel, B., Blair, J. A., Gonzalez, B., Nazif, T. M., Feldman, M. E., Aizenstein, B., Hoffman, R., Williams, R. L., Shokat, K. M., & Knight, Z. A.
- Venue
- Nature Chemical Biology
- Published
- 2008-10-12
- Volume
- 4
- Issue
- 11
- Pages
- 691-699
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2103445331
- Cited by
- 440
- References
- 13
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- green
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- Apsel, B., Blair, J. A., Gonzalez, B., Nazif, T. M., Feldman, M. E., Aizenstein, B., Hoffman, R., Williams, R. L., Shokat, K. M., & Knight, Z. A. (2008). Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chemical Biology. https://doi.org/10.1038/nchembio.117
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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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