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Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents
Open accessAbstract
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.
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Cites
HSP90 and the chaperoning of cancer
Whitesell, L., & Lindquist, S. L. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1716 · Cited by 2,502
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Woodhead, A. J., Angove, H., Carr, M. G., Chessari, G., Congreve, M., Coyle, J. E., Cosme, J., Graham, B., Day, P. J., Downham, R., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100060b · Cited by 264
Heat-shock proteins: chaperoning DNA repair
Dubrez, L., Causse, S., Borges Bonan, N., Dumétier, B., & Garrido, C. (2020) · Oncogene · doi:10.1038/s41388-019-1016-y · Cited by 224
Old and New Approaches to Target the Hsp90 Chaperone
Sanchez, J., Carter, T. R., Cohen, M. S., & Blagg, B. S. J. (2020) · Current Cancer Drug Targets · doi:10.2174/1568009619666191202101330 · Cited by 183
Pan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances
Yu, J., Zhang, C., & Song, C. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114516 · Cited by 51
Metadata
- Authors
- Huang, K. H., Veal, J. M., Fadden, R. P., Rice, J. W., Eaves, J., Strachan, J.-P., Barabasz, A. F., Foley, B. E., Barta, T. E., Ma, W., Silinski, M. A., Hu, M., Partridge, J. M., Scott, A., DuBois, L. G., Freed, T., Steed, P. M., Ommen, A. J., Smith, E. D., Hughes, P. F., Woodward, A. R., Hanson, G. J., McCall, W. S., Markworth, C. J., Hinkley, L., Jenks, M., Geng, L., Lewis, M., Otto, J., Pronk, B., Verleysen, K., & Hall, S. E.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-06-24
- Volume
- 52
- Issue
- 14
- Pages
- 4288-4305
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1966229978
- Cited by
- 192
- References
- 1
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Huang, K. H., Veal, J. M., Fadden, R. P., Rice, J. W., Eaves, J., Strachan, J.-P., Barabasz, A. F., Foley, B. E., Barta, T. E., Ma, W., Silinski, M. A., Hu, M., Partridge, J. M., Scott, A., DuBois, L. G., Freed, T., Steed, P. M., Ommen, A. J., Smith, E. D., . . . Hall, S. E. (2009). Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm900230j
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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.
