Adenosine mimetics as inhibitors of NAD+-dependent histone deacetylases, from kinase to sirtuin inhibition.


:NAD+-dependent histone deacetylases, sirtuins, cleave acetyl groups from lysines of histones and other proteins to regulate their activity. Identification of potent selective inhibitors would help to elucidate sirtuin biology and could lead to useful therapeutic agents. NAD+ has an adenosine moiety that is also present in the kinase cofactor ATP. Kinase inhibitors based upon adenosine mimesis may thus also target NAD+-dependent enzymes. We present a systematic approach using adenosine mimics from one cofactor class (kinase inhibitors) as a viable method to generate new lead structures in another cofactor class (sirtuin inhibitors). Our findings have broad implications for medicinal chemistry and specifically for sirtuin inhibitor design. Our results also raise a question as to whether selectivity profiling for kinase inhibitors should be limited to ATP-dependent targets.


J Med Chem


Trapp J,Jochum A,Meier R,Saunders L,Marshall B,Kunick C,Verdin E,Goekjian P,Sippl W,Jung M




Has Abstract


2006-12-14 00:00:00












  • Comparative molecular field analysis and comparative molecular similarity indices analysis of thalidomide analogues as angiogenesis inhibitors.

    abstract::Thalidomide, 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione, has been shown to inhibit angiogenesis, the formation of new blood vessels from existing vasculature. As a result, there is renewed interest in this drug as a potential therapy for solid tumors. Thalidomide forms a number of metabolites and has been ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lepper ER,Ng SS,Gütschow M,Weiss M,Hauschildt S,Hecker TK,Luzzio FA,Eger K,Figg WD

    更新日期:2004-04-22 00:00:00

  • Development of tetrahydroisoquinoline-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities.

    abstract::Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibit...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Zhang Y,Feng J,Jia Y,Wang X,Zhang L,Liu C,Fang H,Xu W

    更新日期:2011-04-28 00:00:00

  • Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

    abstract::A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3K...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Thakur A,Tawa GJ,Henderson MJ,Danchik C,Liu S,Shah P,Wang AQ,Dunn G,Kabir M,Padilha EC,Xu X,Simeonov A,Kharbanda S,Stone R,Grewal G

    更新日期:2020-04-23 00:00:00

  • Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors.

    abstract::Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Borišek J,Vizovišek M,Sosnowski P,Turk B,Turk D,Mohar B,Novič M

    更新日期:2015-09-10 00:00:00

  • Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 -hydroxyprogesterones.

    abstract::Synthesis and biological activity of 17-esters of 6-dehydro-16-methylene-17 alpha-hydroxyprogesterone are presented. A systematic study of the influence of the alteration of halogen at 6 and the acyl group at 17 on the progestational and antiandrogenic activities of the resulting structures is described. A convenien...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Shapiro EL,Weber L,Harris H,Miskowicz C,Neri R,Herzog HL

    更新日期:1972-07-01 00:00:00

  • Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.

    abstract::Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizure...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kelley JL,Davis RG,McLean EW,Glen RC,Soroko FE,Cooper BR

    更新日期:1995-09-15 00:00:00

  • Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations.

    abstract::A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Huang D,Lüthi U,Kolb P,Edler K,Cecchini M,Audetat S,Barberis A,Caflisch A

    更新日期:2005-08-11 00:00:00

  • Substituted-vinyl hydroxytriarylethylenes, 1-[4-[2-(diethylamino) ethoxy]phenyl]-1-(4-hydroxyphenyl)-2-phenylethylenes: synthesis and effects on MCF 7 breast cancer cell proliferation.

    abstract::A series of triarylethylene compounds related to 4-hydroxyclomiphene (2) in which the vinyl Cl substituent was replaced by ethyl (5), Br (6), H (7), CN (8), or NO2 (9) substituents were synthesized to facilitate studies of the molecular actions of synthetic nonsteroidal antiestrogens. The relative binding affinities o...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Ruenitz PC,Bagley JR,Watts CK,Hall RE,Sutherland RL

    更新日期:1986-12-01 00:00:00

  • Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.

    abstract::Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Pellicciari R,Gioiello A,Costantino G,Sadeghpour BM,Rizzo G,Meyer U,Parks DJ,Entrena-Guadix A,Fiorucci S

    更新日期:2006-07-13 00:00:00

  • MolDock: a new technique for high-accuracy molecular docking.

    abstract::In this article we introduce a molecular docking algorithm called MolDock. MolDock is based on a new heuristic search algorithm that combines differential evolution with a cavity prediction algorithm. The docking scoring function of MolDock is an extension of the piecewise linear potential (PLP) including new hydrogen...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Thomsen R,Christensen MH

    更新日期:2006-06-01 00:00:00

  • Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality.

    abstract::Multidrug-resistant Staphylococcus aureus, including MRSA (methicillin-resistant) and VRSA (vancomycin-resistant), causes serious healthcare-associated infections, even sepsis and death. Here, we identified six novel cathelicidins (CATHPb1-6) from Python bivittatu, and CATHPb1 displayed the best in vitro pharmacologic...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Cai S,Qiao X,Feng L,Shi N,Wang H,Yang H,Guo Z,Wang M,Chen Y,Wang Y,Yu H

    更新日期:2018-03-08 00:00:00

  • Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.

    abstract::On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Nagle A,Wu T,Kuhen K,Gagaring K,Borboa R,Francek C,Chen Z,Plouffe D,Lin X,Caldwell C,Ek J,Skolnik S,Liu F,Wang J,Chang J,Li C,Liu B,Hollenbeck T,Tuntland T,Isbell J,Chuan T,Alper PB,Fischli C,Brun R,Lakshm

    更新日期:2012-05-10 00:00:00

  • Synthesis and beta-adrenergic blocking activity of new aliphatic oxime ethers.

    abstract::New beta-adrenergic blocking agents, most of which do not contain an aromatic nucleus, were synthesized. They were derived either from alkylamino-aliphatic oxime ethers or alkylamino-aliphatic ethers. Most active among these are O-[3-(tert-butylamino)-2-hydroxypropyl]acetoxime (8; trachea pA2 = 7.65) and 1-isobutoxy-3...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Leclerc G,Bieth N,Schwartz J

    更新日期:1980-06-01 00:00:00

  • Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding.

    abstract::Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considere...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Menichincheri M,Albanese C,Alli C,Ballinari D,Bargiotti A,Caldarelli M,Ciavolella A,Cirla A,Colombo M,Colotta F,Croci V,D'Alessio R,D'Anello M,Ermoli A,Fiorentini F,Forte B,Galvani A,Giordano P,Isacchi A,Martina K,

    更新日期:2010-10-28 00:00:00

  • Ketanserin analogues: structure-affinity relationships for 5-HT2 and 5-HT1C serotonin receptor binding.

    abstract::Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Herndon JL,Ismaiel A,Ingher SP,Teitler M,Glennon RA

    更新日期:1992-12-25 00:00:00

  • Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine.

    abstract::CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Å resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of C...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Smith EW,Liu Y,Getschman AE,Peterson FC,Ziarek JJ,Li R,Volkman BF,Chen Y

    更新日期:2014-11-26 00:00:00

  • Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines.

    abstract::Variation of the bridge linking the heterocyclic ring and p-aminobenzoyl-L-glutamate portions of our previously described classical 2,4-diaminofuro[2,3-d]pyrimidines 1 and 2 are reported as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and as antitumor agents. Specifically -CH2CH2- and -CH...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Gangjee A,Devraj R,McGuire JJ,Kisliuk RL

    更新日期:1995-09-15 00:00:00

  • Synthesis, structure, dopamine transporter affinity, and dopamine uptake inhibition of 6-alkyl-3-benzyl-2-[(methoxycarbonyl)methyl]tropane derivatives.

    abstract::A series of 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (Ki) for the DAT of the 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl) methyl]tropane analogues was determined by inhibition...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Lomenzo SA,Izenwasser S,Katz JL,Terry PD,Zhu N,Klein CL,Trudell ML

    更新日期:1997-12-19 00:00:00

  • Predicting binding modes from free energy calculations.

    abstract::To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Nervall M,Hanspers P,Carlsson J,Boukharta L,Aqvist J

    更新日期:2008-05-08 00:00:00

  • A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant.

    abstract::Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously des...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Giffin MJ,Heaslet H,Brik A,Lin YC,Cauvi G,Wong CH,McRee DE,Elder JH,Stout CD,Torbett BE

    更新日期:2008-10-23 00:00:00

  • Preparation, DNA binding, and in vitro cytotoxicity of a pair of enantiomeric platinum(II) complexes, [(R)- and (S)-3-aminohexahydroazepine]dichloroplatinum(II). Crystal structure of the S enantiomer.

    abstract::A pair of enantiomeric Pt(II) complexes, [Pt(R-ahaz)Cl2] and [Pt(S-ahaz)Cl2] (ahaz = 3-aminohexahydroazepine), has been investigated for their ability to bind enantioselectively to DNA. Improved synthetic procedures were developed for preparing both the ligands and the Pt complexes. The structure of the complex of the...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Fenton RR,Easdale WJ,Er HM,O'Mara SM,McKeage MJ,Russell PJ,Hambley TW

    更新日期:1997-03-28 00:00:00

  • Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A recepto

    abstract::Here we describe the design, synthesis, and pharmacological profile of 5-HT(1A) receptor ligands related to 1 (WAY-100635). The cyclohexyl moiety in 1 and its O-desmethylated analogue 3 were replaced by the bridgehead iodinated bridge-fused rings: adamantyl, cubyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptyl. All ana...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Al Hussainy R,Verbeek J,van der Born D,Braker AH,Leysen JE,Knol RJ,Booij J,Herscheid JK

    更新日期:2011-05-26 00:00:00

  • Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

    abstract::Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Kettle JG,Bagal SK,Bickerton S,Bodnarchuk MS,Breed J,Carbajo RJ,Cassar DJ,Chakraborty A,Cosulich S,Cumming I,Davies M,Eatherton A,Evans L,Feron L,Fillery S,Gleave ES,Goldberg FW,Harlfinger S,Hanson L,Howard M,Howe

    更新日期:2020-05-14 00:00:00

  • Synthesis of 1-(2-aminophenyl)isoquinolines and the biological activity of their cis-dichloro platinum(II) complexes.

    abstract::The broad biological effects of isoquinolines prompted us to use them as chelating, nonleaving ligands in cis-platinum(II) antitumor complexes. The synthesis of several 1-(2-aminophenyl)isoquinoline derivatives with different levels of hydrogenation and varying substitution of the phenyl ring is reported. These compou...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: von Nussbaum F,Miller B,Wild S,Hilger CS,Schumann S,Zorbas H,Beck W,Steglich W

    更新日期:1999-09-09 00:00:00

  • Fatty acid amide hydrolase inhibitors from virtual screening of the endocannabinoid system.

    abstract::The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitor...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Saario SM,Poso A,Juvonen RO,Järvinen T,Salo-Ahen OM

    更新日期:2006-07-27 00:00:00

  • On the histone lysine methyltransferase activity of fungal metabolite chaetocin.

    abstract::Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally rela...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Cherblanc FL,Chapman KL,Reid J,Borg AJ,Sundriyal S,Alcazar-Fuoli L,Bignell E,Demetriades M,Schofield CJ,DiMaggio PA Jr,Brown R,Fuchter MJ

    更新日期:2013-11-14 00:00:00

  • Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB.

    abstract::The transcription factor nuclear factor kappaB (NF-kappaB), which regulates expression of numerous antiinflammatory genes as well as genes that promote development of the prosurvival, antiapoptotic state is up-regulated in many cancer cells. The natural product resveratrol, a polyphenolic trans-stilbene, has numerous ...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Heynekamp JJ,Weber WM,Hunsaker LA,Gonzales AM,Orlando RA,Deck LM,Jagt DL

    更新日期:2006-11-30 00:00:00

  • Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3.

    abstract::The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Muth F,El-Gokha A,Ansideri F,Eitel M,Döring E,Sievers-Engler A,Lange A,Boeckler FM,Lämmerhofer M,Koch P,Laufer SA

    更新日期:2017-01-26 00:00:00

  • Synthesis of new acridone derivatives, inhibitors of NS3 helicase, which efficiently and specifically inhibit subgenomic HCV replication.

    abstract::A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC(50) from 1.5 to 20 microM). T...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Stankiewicz-Drogoń A,Dörner B,Erker T,Boguszewska-Chachulska AM

    更新日期:2010-04-22 00:00:00

  • Synthesis and antihypertensive activity of 3-[(substituted-carbonyl)amino]-2H-1-benzopyrans.

    abstract::The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbon...

    journal_title:Journal of medicinal chemistry

    pub_type: 杂志文章


    authors: Cassidy F,Evans JM,Hadley MS,Haladij AH,Leach PE,Stemp G

    更新日期:1992-05-01 00:00:00