The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Chemical genetic discovery of targets and anti-targets for cancer polypharmacology
Open accessAbstract
The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the ‘anti-target’ Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine neoplasia type 2 models. Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems pharmacology approach towards developing compounds with a maximal therapeutic index.
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Comprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735
Network motifs: theory and experimental approaches
Alon, U. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2102 · Cited by 3,279
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681
A quantitative analysis of kinase inhibitor selectivity
Karaman, M. W., Herrgard, S., Treiber, D. K., Gallant, P., Atteridge, C. E., Campbell, B. T., Chan, K. W., Ciceri, P., Davis, M. I., Edeen, P. T., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1358 · Cited by 2,466
Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34739 · Cited by 1,381
Targeting the cancer kinome through polypharmacology
Knight, Z. A., Lin, H., & Shokat, K. M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2787 · Cited by 674 · cited 1×
“By contrast, most drugs approved for clinical use have multiple targets 11–13 .”
Cited by
Roth, B. L. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.040 · Cited by 1,742
Polypharmacology: Challenges and Opportunities in Drug Discovery: Miniperspective
Anighoro, A., Bajorath, J., & Rastelli, G. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5006463 · Cited by 1,131
Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds
Proschak, E., Stark, H., & Merk, D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00760 · Cited by 498
Gene Therapy Tools for Brain Diseases
Ingusci, S., Verlengia, G., Soukupova, M., Zucchini, S., & Simonato, M. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00724 · Cited by 158
Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model
La Marca, J. E., & Richardson, H. E. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00042 · Cited by 139
Metadata
- Authors
- Dar, A. C., Das, T. K., Shokat, K. M., & Cagan, R. L.
- Venue
- Nature
- Published
- 2012-06
- Volume
- 486
- Issue
- 7401
- Pages
- 80-84
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1972577475
- Cited by
- 333
- References
- 6
- FWCI
- 24.32
- Type
- journal article
- Language
- en
- Open access
- green
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