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Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
J Med Chem. 2013 May 09; 56(9):3666-79.JM

Abstract

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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Publisher Full Text (DOI)

Authors+Show Affiliations

Disch JS
Sirtris a GSK Company, Cambridge, Massachusetts, United States. jdisch92@gmail.com
Evindar G
No affiliation info available
Chiu CH
No affiliation info available
Blum CA
No affiliation info available
Dai H
No affiliation info available
Jin L
No affiliation info available
Schuman E
No affiliation info available
Lind KE
No affiliation info available
Belyanskaya SL
No affiliation info available
Deng J
No affiliation info available
Coppo F
No affiliation info available
Aquilani L
No affiliation info available
Graybill TL
No affiliation info available
Cuozzo JW
No affiliation info available
Lavu S
No affiliation info available
Mao C
No affiliation info available
Vlasuk GP
No affiliation info available
Perni RB
No affiliation info available

MeSH

Drug DiscoveryHumansModels, MolecularProtein ConformationPyrimidinesSirtuin 1Sirtuin 2Sirtuin 3Sirtuins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23570514

Citation

Disch, Jeremy S., et al. "Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3." Journal of Medicinal Chemistry, vol. 56, no. 9, 2013, pp. 3666-79.
Disch JS, Evindar G, Chiu CH, et al. Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. J Med Chem. 2013;56(9):3666-79.
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. (2013). Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. Journal of Medicinal Chemistry, 56(9), 3666-79. https://doi.org/10.1021/jm400204k
Disch JS, et al. Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3. J Med Chem. 2013 May 9;56(9):3666-79. PubMed PMID: 23570514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. AU - Disch,Jeremy S, AU - Evindar,Ghotas, AU - Chiu,Cynthia H, AU - Blum,Charles A, AU - Dai,Han, AU - Jin,Lei, AU - Schuman,Eli, AU - Lind,Kenneth E, AU - Belyanskaya,Svetlana L, AU - Deng,Jianghe, AU - Coppo,Frank, AU - Aquilani,Leah, AU - Graybill,Todd L, AU - Cuozzo,John W, AU - Lavu,Siva, AU - Mao,Cheney, AU - Vlasuk,George P, AU - Perni,Robert B, Y1 - 2013/04/29/ PY - 2013/4/11/entrez PY - 2013/4/11/pubmed PY - 2013/7/10/medline SP - 3666 EP - 79 JF - Journal of medicinal chemistry JO - J Med Chem VL - 56 IS - 9 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/23570514/Discovery_of_thieno[32_d]pyrimidine_6_carboxamides_as_potent_inhibitors_of_SIRT1_SIRT2_and_SIRT3_ DB - PRIME DP - Unbound Medicine ER -