当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.

A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors.

Abstract：

:The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a variety of KAc-binding fragments with a tetrahydroquinoline scaffold that makes optimal interactions with the LPF shelf, imparting enhanced potency and selectivity to the hybridized ligand. To demonstrate the utility of our hybridization approach, two analogues containing unique Asn binders and the optimized tetrahydroquinoline moiety were rapidly optimized to yield single-digit nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1) and the broader bromodomain family.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Bronner SM,Murray J,Romero FA,Lai KW,Tsui V,Cyr P,Beresini MH,de Leon Boenig G,Chen Z,Choo EF,Clark KR,Crawford TD,Jayaram H,Kaufman S,Li R,Li Y,Liao J,Liang X,Liu W,Ly J,Maher J,Wai J,Wang F,Zheng A,Zhu X

doi

10.1021/acs.jmedchem.7b01372

subject

Has Abstract

pub_date

2017-12-28 00:00:00

pages

10151-10171

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

60

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • How are fragments optimized? A retrospective analysis of 145 fragment optimizations.

    abstract：:Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipoph...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm301851v

    authors： Ferenczy GG,Keserű GM

    更新日期：2013-03-28 00:00:00

  • Quinazolines and 1,4-benzodiazepines. 90. Structure-activity relationship between substituted 2-amino-N-(2-benzoyl-4-chlorophenyl)acetamides and 1,4-benzodiazepinones.

    abstract：:The syntheses of 2-amino-N-(2-benzoyl)-4-chlorophenyl)acetamides are reported. The pharmacological properties of these compounds were compared with data obtained from the corresponding cyclized products [5-(2,6-dichlorophenyl)-1,4-benzodiazepin-2-ones]. Evidence is presented which suggests that the central nervous sys...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00351a009

    authors： Fryer RI,Leimgruber W,Trybulski EJ

    更新日期：1982-09-01 00:00:00

  • Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity.

    abstract：:Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional aff...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b01626

    authors： Peterson K,Kumar R,Stenström O,Verma P,Verma PR,Håkansson M,Kahl-Knutsson B,Zetterberg F,Leffler H,Akke M,Logan DT,Nilsson UJ

    更新日期：2018-02-08 00:00:00

  • Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies.

    abstract：:We previously reported a novel class of stabilized immune-modulatory RNA (SIMRA) compounds that activates TLR8 or both TLR7 and TLR8 depending on the nucleotide composition and chemical modifications incorporated. In the present study, to identify TLR7-selective agonists, we designed and synthesized novel SIMRA compou...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm901145s

    authors： Lan T,Dai M,Wang D,Zhu FG,Kandimalla ER,Agrawal S

    更新日期：2009-11-12 00:00:00

  • Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents.

    abstract：:New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-a]pyridines 7-9. The side chain at the 3-position was elaborated...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00129a028

    authors： Starrett JE Jr,Montzka TA,Crosswell AR,Cavanagh RL

    更新日期：1989-09-01 00:00:00

  • Structure-based design, synthesis, and antimicrobial activity of indazole-derived SAH/MTA nucleosidase inhibitors.

    abstract：:The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spec...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0302039

    authors： Li X,Chu S,Feher VA,Khalili M,Nie Z,Margosiak S,Nikulin V,Levin J,Sprankle KG,Tedder ME,Almassy R,Appelt K,Yager KM

    更新日期：2003-12-18 00:00:00

  • Antibacterial inhibitors of Gram-positive thymidylate kinase: structure-activity relationships and chiral preference of a new hydrophobic binding region.

    abstract：:Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was emp...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm500463c

    authors： Kawatkar SP,Keating TA,Olivier NB,Breen JN,Green OM,Guler SY,Hentemann MF,Loch JT,McKenzie AR,Newman JV,Otterson LG,Martínez-Botella G

    更新日期：2014-06-12 00:00:00

  • Novel triazole ribonucleoside down-regulates heat shock protein 27 and induces potent anticancer activity on drug-resistant pancreatic cancer.

    abstract：:A series of novel 3-arylethynyltriazolyl ribonucleosides were synthesized and assessed for their anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaCa-2. Among them, one compound exhibited potent apoptosis-inducing properties and anticancer activity against the pancreatic cancer model MiaPaCa-2...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900960v

    authors： Xia Y,Liu Y,Wan J,Wang M,Rocchi P,Qu F,Iovanna JL,Peng L

    更新日期：2009-10-08 00:00:00

  • 3-Quinolinecarboxamides. A series of novel orally-active antiherpetic agents.

    abstract：:A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00063a008

    authors： Wentland MP,Perni RB,Dorff PH,Brundage RP,Castaldi MJ,Bailey TR,Carabateas PM,Bacon ER,Young DC,Woods MG

    更新日期：1993-05-28 00:00:00

  • Novel quinolizidinyl derivatives as antiarrhythmic agents: 2. Further investigation.

    abstract：:Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100298d

    authors： Tasso B,Budriesi R,Vazzana I,Ioan P,Micucci M,Novelli F,Tonelli M,Sparatore A,Chiarini A,Sparatore F

    更新日期：2010-06-24 00:00:00

  • Isotope effects in enzymatic N-demethylation of tertiary amines.

    abstract：:The N-demethylation of 1-(N-methyl-N-trideuteriomethylamino)-3-phenylpropane (1) by rodent liver homogenates was studied. The ratio of 1-trideuteriomethylamino-3-phenylpropane (2)/1-methylamino-3-phenylpropane (3) was determined by gc-ms. The ratio of 2/3 in the product of N-demethylation of 1 by liver homogenate from...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00238a021

    authors： Abdel-Monem MM

    更新日期：1975-04-01 00:00:00

  • Regulating bioactivity of Cu2+ bis-1,10-phenanthroline artificial metallonucleases with sterically functionalized pendant carboxylates.

    abstract：:The synthetic chemical nuclease, [Cu(1,10-phenanthroline)2](2+), has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is "promiscuous" as it binds both dsDNA and protein biomolecules, without specificity, and induces ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm401465m

    authors： Prisecaru A,McKee V,Howe O,Rochford G,McCann M,Colleran J,Pour M,Barron N,Gathergood N,Kellett A

    更新日期：2013-11-14 00:00:00

  • Synthesis and biological activity of several amino analogues of thymidine.

    abstract：:3',5'-Diamino-3',5'-dideoxythymidine (7) was synthesized via a nine-step synthesis from thymidine in good overall yield. 3'-Amino-3'-deoxythymidine (8) and 5'-amino-5'-deoxythymidine (12) were prepared with a minor modification of the procedure reported by Horwitz and co-workers. Although the 5'-amino analogue 12 had ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：

    authors： Lin TS,Prusoff WH

    更新日期：1978-01-01 00:00:00

  • Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic Bcl-2 proteins.

    abstract：:Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-2...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm070383c

    authors： Tang G,Ding K,Nikolovska-Coleska Z,Yang CY,Qiu S,Shangary S,Wang R,Guo J,Gao W,Meagher J,Stuckey J,Krajewski K,Jiang S,Roller PP,Wang S

    更新日期：2007-07-12 00:00:00

  • Development of Isoselenocyanate Compounds' Syntheses and Biological Applications.

    abstract：:As the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown produc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.8b01698

    authors： Frieben EE,Amin S,Sharma AK

    更新日期：2019-06-13 00:00:00

  • Discovery of Small Molecules as Multi-Toll-like Receptor Agonists with Proinflammatory and Anticancer Activities.

    abstract：:Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00419

    authors： Zhang L,Dewan V,Yin H

    更新日期：2017-06-22 00:00:00

  • Immuno-suppressive effect of blocking the CD28 signaling pathway in T-cells by an active component of Echinacea found by a novel pharmaceutical screening method.

    abstract：:AFTIR (after flowing through immobilized receptor) is a novel method for screening herbal extracts for pharmaceutical properties. Using AFTIR, we identified Cynarin in Echinacea purpurea by its selective binding to chip immobilized CD28, a receptor of T-cells, which is instrumental to immune functioning. The results o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0509039

    authors： Dong GC,Chuang PH,Forrest MD,Lin YC,Chen HM

    更新日期：2006-03-23 00:00:00

  • A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers.

    abstract：:Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal ce...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm4012438

    authors： Millard M,Gallagher JD,Olenyuk BZ,Neamati N

    更新日期：2013-11-27 00:00:00

  • 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Side chain ester derivatives of mevinolin.

    abstract：:Modification of the 2(S)-methylbutyryl moiety of mevinolin led to a series of side chain ester derivatives. A systematic exploration of the structure-activity relationships showed that the introduction of an additional aliphatic group on the carbon alpha to the carbonyl group increased potency. This observation led to...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00155a040

    authors： Hoffman WF,Alberts AW,Anderson PS,Chen JS,Smith RL,Willard AK

    更新日期：1986-05-01 00:00:00

  • Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines.

    abstract：:Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatina...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980475p

    authors： Szardenings AK,Antonenko V,Campbell DA,DeFrancisco N,Ida S,Shi L,Sharkov N,Tien D,Wang Y,Navre M

    更新日期：1999-04-22 00:00:00

  • A 1H NMR study of the interactions and conformations of rationally designed brodimoprim analogues in complexes with Lactobacillus casei dihydrofolate reductase.

    abstract：:A consideration of the detailed structural information available from X-ray crystallographic and NMR studies on complexes of dihydrofolate reductase with inhibitors has led to the design of trimethoprim analogues with improved binding properties. Computer graphic techniques have been used to predict which substituent ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00378a025

    authors： Birdsall B,Feeney J,Pascual C,Roberts GC,Kompis I,Then RL,Müller K,Kroehn A

    更新日期：1984-12-01 00:00:00

  • Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P5) Agonist for the Potential Treatment of Neurodegenerative Disorders.

    abstract：:S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules wit...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00928

    authors： Hobson AD,Harris CM,van der Kam EL,Turner SC,Abibi A,Aguirre AL,Bousquet P,Kebede T,Konopacki DB,Gintant G,Kim Y,Larson K,Maull JW,Moore NS,Shi D,Shrestha A,Tang X,Zhang P,Sarris KK

    更新日期：2015-12-10 00:00:00

  • Novel calcium antagonists. Synthesis and structure-activity relationship studies of benzothiazoline derivatives.

    abstract：:A series of novel compounds having a benzothiazoline skeleton was studied for their structure-activity relationship (SAR) with respect to Ca2+ antagonistic activity. As test compounds, analogues of 3-acyl-2-arylbenzothiazolines (3) were synthesized. Benzothiazoline derivatives (3) exerted higher Ca2+ antagonistic acti...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00400a006

    authors： Yamamoto K,Fujita M,Tabashi K,Kawashima Y,Kato E,Oya M,Iso T,Iwao J

    更新日期：1988-05-01 00:00:00

  • Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.

    abstract：:The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antid...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm2015952

    authors： Chao B,Tong XK,Tang W,Li DW,He PL,Garcia JM,Zeng LM,Gao AH,Yang L,Li J,Nan FJ,Jacobs M,Altmeyer R,Zuo JP,Hu YH

    更新日期：2012-04-12 00:00:00

  • Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule.

    abstract：:Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.7b00324

    authors： Cheng X,Merz KH,Vatter S,Zeller J,Muehlbeyer S,Thommet A,Christ J,Wölfl S,Eisenbrand G

    更新日期：2017-06-22 00:00:00

  • Development of predictive retention-activity relationship models of tricyclic antidepressants by micellar liquid chromatography.

    abstract：:The distribution of tricyclic antidepressants from plasma to brain, where these drugs exert their main clinical action, and other organs is related to transport events across the cell membranes of the different tissues. It could be expected that all the molecular features that condition the transport processes (mainly...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9910369

    authors： Quiñones-Torrelo C,Sagrado S,Villanueva-Camañas RM,Medina-Hernández MJ

    更新日期：1999-08-12 00:00:00

  • Discovery of a bulky 2-tert-butyl group containing primaquine analogue that exhibits potent blood-schizontocidal antimalarial activities and complete elimination of methemoglobin toxicity.

    abstract：:To eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where C-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. Compound 2 [R = C(CH(3))(3)] of the series has produced excellent antimalarial efficacy against P. be...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0304562

    authors： Jain M,Vangapandu S,Sachdeva S,Singh S,Singh PP,Jena GB,Tikoo K,Ramarao P,Kaul CL,Jain R

    更新日期：2004-01-15 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

    doi：10.1021/jm980434t

    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

  • Synthesis of low-hemolytic antimicrobial dehydropeptides based on gramicidin s.

    abstract：:The synthesis and biological activity of a novel cyclic beta-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(beta-3-pyridyl)-alpha,beta-dehydroalanine (DeltaZ3Pal) residues at the 4 and 4' positions (2), was synthesized by solution-phase methodologi...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm061051v

    authors： Yamada K,Shinoda SS,Oku H,Komagoe K,Katsu T,Katakai R

    更新日期：2006-12-28 00:00:00

  • Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.

    abstract：:In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulti...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.5b00774

    authors： Zhao Z,Pissarnitski DA,Josien HB,Wu WL,Xu R,Li H,Clader JW,Burnett DA,Terracina G,Hyde L,Lee J,Song L,Zhang L,Parker EM

    更新日期：2015-11-25 00:00:00