The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3
Open accessAbstract
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.
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Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
Tissue-specific regulation of SIRT1 by calorie restriction
Chen, D., Bruno, J., Easlon, E., Lin, S.-J., Cheng, H.-L., Alt, F. W., & Guarente, L. (2008) · Genes & Development · doi:10.1101/gad.1650608 · Cited by 567
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A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
Beno, B. R., Yeung, K.-S., Bartberger, M. D., Pennington, L. D., & Meanwell, N. A. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501853m · Cited by 772
DNA-encoded chemistry: enabling the deeper sampling of chemical space
Goodnow, R. A., Dumelin, C. E., & Keefe, A. D. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.213 · Cited by 621
Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target
Zhang, J., Xiang, H., Liu, J., Chen, Y., He, R.-R., & Liu, B. (2020) · Theranostics · doi:10.7150/thno.45922 · Cited by 503
Sirtuin activators and inhibitors: Promises, achievements, and challenges
Dai, H., Sinclair, D. A., Ellis, J. L., & Steegborn, C. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.03.004 · Cited by 463
“A potent Sirtuin inhibitor that exploits the C-site and which shows some isoform selectivity is Ex-527 (Table 1).”
BackgroundInfluentialSelf-citationSirtuin functions and modulation: from chemistry to the clinic
Carafa, V., Rotili, D., Forgione, M., Cuomo, F., Serretiello, E., Hailu, G. S., Jarho, E., Lahtela-Kakkonen, M., Mai, A., & Altucci, L. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0224-3 · Cited by 387
Metadata
- Authors
- Disch, J. S., Evindar, G., Chiu, C. H., Blum, C. A., Dai, H., Jin, L., Schuman, E., Lind, K. E., Belyanskaya, S. L., Deng, J., Coppo, F., Aquilani, L., Graybill, T. L., Cuozzo, J. W., Lavu, S., Mao, C., Vlasuk, G. P., & Perni, R. B.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-04-29
- Volume
- 56
- Issue
- 9
- Pages
- 3666-3679
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2051960831
- Cited by
- 194
- References
- 3
- FWCI
- 12.27
- Type
- journal article
- Language
- en
- Open access
- green
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