4jt9 Citations

Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3.


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 analogs 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.

Reviews citing this publication (12)

  1. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Goodnow RA, Dumelin CE, Keefe AD. Nat Rev Drug Discov 16 131-147 (2017)
  2. The Current State of NAD(+) -Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets. Schiedel M, Robaa D, Rumpf T, Sippl W, Jung M. Med Res Rev (2017)
  3. Using mitochondrial sirtuins as drug targets: disease implications and available compounds. Gertz M, Steegborn C. Cell. Mol. Life Sci. 73 2871-2896 (2016)
  4. Human sirtuins: Structures and flexibility. Sacconnay L, Carrupt PA, Nurisso A. J. Struct. Biol. 196 534-542 (2016)
  5. DNA-encoded chemical libraries: foundations and applications in lead discovery. Zimmermann G, Neri D. Drug Discov. Today 21 1828-1834 (2016)
  6. Sirtuin functions and modulation: from chemistry to the clinic. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, Jarho E, Lahtela-Kakkonen M, Mai A, Altucci L. Clin Epigenetics 8 61 (2016)
  7. Fidelity by design: Yoctoreactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery. Blakskjaer P, Heitner T, Hansen NJ. Curr Opin Chem Biol 26 62-71 (2015)
  8. Schistosome sirtuins as drug targets. Lancelot J, Cabezas-Cruz A, Caby S, Marek M, Schultz J, Romier C, Sippl W, Jung M, Pierce RJ. Future Med Chem 7 765-782 (2015)
  9. The chemical biology of sirtuins. Chen B, Zang W, Wang J, Huang Y, He Y, Yan L, Liu J, Zheng W. Chem Soc Rev 44 5246-5264 (2015)
  10. Chemical ligation methods for the tagging of DNA-encoded chemical libraries. Keefe AD, Clark MA, Hupp CD, Litovchick A, Zhang Y. Curr Opin Chem Biol 26 80-88 (2015)
  11. New assays and approaches for discovery and design of Sirtuin modulators. Schutkowski M, Fischer F, Roessler C, Steegborn C. Expert Opin Drug Discov 9 183-199 (2014)
  12. Sirtuin inhibitors as anticancer agents. Hu J, Jing H, Lin H. Future Med Chem 6 945-966 (2014)

Articles citing this publication (39)

  1. Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Dai H, Case AW, Riera TV, Considine T, Lee JE, Hamuro Y, Zhao H, Jiang Y, Sweitzer SM, Pietrak B, Schwartz B, Blum CA, Disch JS, Caldwell R, Szczepankiewicz B, Oalmann C, Yee Ng P, White BH, Casaubon R, Narayan R, Koppetsch K, Bourbonais F, Wu B, Wang J, Qian D, Jiang F, Mao C, Wang M, Hu E, Wu JC, Perni RB, Vlasuk GP, Ellis JL. Nat Commun 6 7645 (2015)
  2. Structural basis for potent inhibition of SIRT2 deacetylase by a macrocyclic peptide inducing dynamic structural change. Yamagata K, Goto Y, Nishimasu H, Morimoto J, Ishitani R, Dohmae N, Takeda N, Nagai R, Komuro I, Suga H, Nureki O. Structure 22 345-352 (2014)
  3. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Oláh J, Ladwein KI, Schmidtkunz K, Gajer M, Pannek M, Steegborn C, Sinclair DA, Gerhardt S, Ovádi J, Schutkowski M, Sippl W, Einsle O, Jung M. Nat Commun 6 6263 (2015)
  4. Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism. Nguyen GT, Schaefer S, Gertz M, Weyand M, Steegborn C. Acta Crystallogr. D Biol. Crystallogr. 69 1423-1432 (2013)
  5. Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists. Kollmann CS, Bai X, Tsai CH, Yang H, Lind KE, Skinner SR, Zhu Z, Israel DI, Cuozzo JW, Morgan BA, Yuki K, Xie C, Springer TA, Shimaoka M, Evindar G. Bioorg. Med. Chem. 22 2353-2365 (2014)
  6. Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library. Litovchick A, Dumelin CE, Habeshian S, Gikunju D, Guié MA, Centrella P, Zhang Y, Sigel EA, Cuozzo JW, Keefe AD, Clark MA. Sci Rep 5 10916 (2015)
  7. Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library. Franzini RM, Ekblad T, Zhong N, Wichert M, Decurtins W, Nauer A, Zimmermann M, Samain F, Scheuermann J, Brown PJ, Hall J, Gräslund S, Schüler H, Neri D. Angew. Chem. Int. Ed. Engl. 54 3927-3931 (2015)
  8. DNA-Encoded Solid-Phase Synthesis: Encoding Language Design and Complex Oligomer Library Synthesis. MacConnell AB, McEnaney PJ, Cavett VJ, Paegel BM. ACS Comb Sci 17 518-534 (2015)
  9. Selection of DNA-encoded small molecule libraries against unmodified and non-immobilized protein targets. Zhao P, Chen Z, Li Y, Sun D, Gao Y, Huang Y, Li X. Angew. Chem. Int. Ed. Engl. 53 10056-10059 (2014)
  10. Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library. Deng H, Zhou J, Sundersingh FS, Summerfield J, Somers D, Messer JA, Satz AL, Ancellin N, Arico-Muendel CC, Sargent Bedard KL, Beljean A, Belyanskaya SL, Bingham R, Smith SE, Boursier E, Carter P, Centrella PA, Clark MA, Chung CW, Davie CP, Delorey JL, Ding Y, Franklin GJ, Grady LC, Herry K, Hobbs C, Kollmann CS, Morgan BA, Pothier Kaushansky LJ, Zhou Q. ACS Med Chem Lett 6 919-924 (2015)
  11. Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins. Christodoulou MS, Sacchetti A, Ronchetti V, Caufin S, Silvani A, Lesma G, Fontana G, Minicone F, Riva B, Ventura M, Lahtela-Kakkonen M, Jarho E, Zuco V, Zunino F, Martinet N, Dapiaggi F, Pieraccini S, Sironi M, Dalla Via L, Gia OM, Passarella D. Bioorg. Med. Chem. 21 6920-6928 (2013)
  12. Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT). Yang H, Medeiros PF, Raha K, Elkins P, Lind KE, Lehr R, Adams ND, Burgess JL, Schmidt SJ, Knight SD, Auger KR, Schaber MD, Franklin GJ, Ding Y, DeLorey JL, Centrella PA, Mataruse S, Skinner SR, Clark MA, Cuozzo JW, Evindar G. ACS Med Chem Lett 6 531-536 (2015)
  13. Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors. Khanfar MA, Quinti L, Wang H, Choi SH, Kazantsev AG, Silverman RB. Eur J Med Chem 76 414-426 (2014)
  14. Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). Ding Y, O'Keefe H, DeLorey JL, Israel DI, Messer JA, Chiu CH, Skinner SR, Matico RE, Murray-Thompson MF, Li F, Clark MA, Cuozzo JW, Arico-Muendel C, Morgan BA. ACS Med Chem Lett 6 888-893 (2015)
  15. The discovery of a highly selective 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 inhibitor that is neuroprotective in an in vitro Parkinson's disease model. Di Fruscia P, Zacharioudakis E, Liu C, Moniot S, Laohasinnarong S, Khongkow M, Harrison IF, Koltsida K, Reynolds CR, Schmidtkunz K, Jung M, Chapman KL, Steegborn C, Dexter DT, Sternberg MJ, Lam EW, Fuchter MJ. ChemMedChem 10 69-82 (2015)
  16. Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. Hubbard BP, Loh C, Gomes AP, Li J, Lu Q, Doyle TL, Disch JS, Armour SM, Ellis JL, Vlasuk GP, Sinclair DA. Cell Cycle 12 2233-2240 (2013)
  17. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors. Wood ER, Bledsoe R, Chai J, Daka P, Deng H, Ding Y, Harris-Gurley S, Kryn LH, Nartey E, Nichols J, Nolte RT, Prabhu N, Rise C, Sheahan T, Shotwell JB, Smith D, Tai V, Taylor JD, Tomberlin G, Wang L, Wisely B, You S, Xia B, Dickson H. J. Biol. Chem. 290 19681-19696 (2015)
  18. A DNA-templated synthesis of encoded small molecules by DNA self-assembly. Cao C, Zhao P, Li Z, Chen Z, Huang Y, Bai Y, Li X. Chem. Commun. (Camb.) 50 10997-10999 (2014)
  19. Simple N(ε)-thioacetyl-lysine-containing cyclic peptides exhibiting highly potent sirtuin inhibition. Huang Y, Liu J, Yan L, Zheng W. Bioorg. Med. Chem. Lett. 26 1612-1617 (2016)
  20. Structure-Based Development of an Affinity Probe for Sirtuin 2. Schiedel M, Rumpf T, Karaman B, Lehotzky A, Gerhardt S, Ovádi J, Sippl W, Einsle O, Jung M. Angew. Chem. Int. Ed. Engl. 55 2252-2256 (2016)
  21. Universal strategies for the DNA-encoding of libraries of small molecules using the chemical ligation of oligonucleotide tags. Litovchick A, Clark MA, Keefe AD. Artif DNA PNA XNA 5 e27896 (2014)
  22. Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins. Franzini RM, Nauer A, Scheuermann J, Neri D. Chem. Commun. (Camb.) 51 8014-8016 (2015)
  23. Selectivity hot-spots of sirtuin catalytic cores. Parenti MD, Bruzzone S, Nencioni A, Del Rio A. Mol Biosyst 11 2263-2272 (2015)
  24. An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening. MacConnell AB, Price AK, Paegel BM. ACS Comb Sci 19 181-192 (2017)
  25. Human SIRT3 tripeptidic inhibitors containing N(ε)-thioacetyl-lysine. Chen B, Wang J, Huang Y, Zheng W. Bioorg. Med. Chem. Lett. 25 3481-3487 (2015)
  26. Molecular modelling studies of sirtuin 2 inhibitors using three-dimensional structure-activity relationship analysis and molecular dynamics simulations. Chuang YC, Chang CH, Lin JT, Yang CN. Mol Biosyst 11 723-733 (2015)
  27. Design, preparation, and selection of DNA-encoded dynamic libraries. Li G, Zheng W, Chen Z, Zhou Y, Liu Y, Yang J, Huang Y, Li X. Chem Sci 6 7097-7104 (2015)
  28. Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors. Yang L, Ma X, Yuan C, He Y, Li L, Fang S, Xia W, He T, Qian S, Xu Z, Li G, Wang Z. Eur J Med Chem 134 230-241 (2017)
  29. Use of the Monte Carlo Method for OECD Principles-Guided QSAR Modeling of SIRT1 Inhibitors. Kumar A, Chauhan S. Arch. Pharm. (Weinheim) 350 (2017)
  30. Cyclic peptide-based potent human SIRT6 inhibitors. Liu J, Zheng W. Org. Biomol. Chem. 14 5928-5935 (2016)
  31. Virtual screening approach of sirtuin inhibitors results in two new scaffolds. Kokkonen P, Kokkola T, Suuronen T, Poso A, Jarho E, Lahtela-Kakkonen M. Eur J Pharm Sci 76 27-32 (2015)
  32. Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors. Therrien E, Larouche G, Nguyen N, Rahil J, Lemieux AM, Li Z, Fournel M, Yan TP, Landry AJ, Lefebvre S, Wang JJ, MacBeth K, Heise C, Nguyen A, Besterman JM, Déziel R, Wahhab A. Bioorg. Med. Chem. Lett. 25 2514-2518 (2015)
  33. Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products. Sun Y, Zhou H, Zhu H, Leung SW. Sci Rep 6 19312 (2016)
  34. A potent IκB kinase-β inhibitor labeled with carbon-14 and deuterium. Latli B, Eriksson M, Hrapchak M, Busacca CA, Senanayake CH. J Labelled Comp Radiopharm 59 300-304 (2016)
  35. Cyclic peptide-based potent and selective SIRT1/2 dual inhibitors harboring Nε-thioacetyl-lysine. Chen D, Zheng W. Bioorg. Med. Chem. Lett. 26 5234-5239 (2016)
  36. Access to functionalized thienopyridines via a reagent-capsule-assisted coupling, thiolation and cyclization cascade sequence. Cai J, Huang S, He R, Chen L, Chen D, Jiang S, Li B, Li Y. Org. Biomol. Chem. 15 333-337 (2017)
  37. Bivalent SIRT1 inhibitors. Wang J, Zang W, Liu J, Zheng W. Bioorg. Med. Chem. Lett. 27 180-186 (2017)
  38. Unsupervised pharmacophore modeling combined with QSAR analyses revealed novel low micromolar SIRT2 inhibitors. Khanfar MA, Taha MO. J. Mol. Recognit. (2017)
  39. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. Machutta CA, Kollmann CS, Lind KE, Bai X, Chan PF, Huang J, Ballell L, Belyanskaya S, Besra GS, Barros-Aguirre D, Bates RH, Centrella PA, Chang SS, Chai J, Choudhry AE, Coffin A, Davie CP, Deng H, Deng J, Ding Y, Dodson JW, Fosbenner DT, Gao EN, Graham TL, Graybill TL, Ingraham K, Johnson WP, King BW, Kwiatkowski CR, Lelièvre J, Li Y, Liu X, Lu Q, Lehr R, Mendoza-Losana A, Martin J, McCloskey L, McCormick P, O'Keefe HP, O'Keeffe T, Pao C, Phelps CB, Qi H, Rafferty K, Scavello GS, Steiginga MS, Sundersingh FS, Sweitzer SM, Szewczuk LM, Taylor A, Toh MF, Wang J, Wang M, Wilkins DJ, Xia B, Yao G, Zhang J, Zhou J, Donahue CP, Messer JA, Holmes D, Arico-Muendel CC, Pope AJ, Gross JW, Evindar G. Nat Commun 8 16081 (2017)