当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.

Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction.

Abstract：

:MLL1 is a histone 3 lysine 4 (H3K4) methyltransferase and a promising new cancer therapeutic target. The catalytic activity of MLL1 is regulated by the formation of a core complex consisting of MLL1, WDR5, RbBP5, and Ash2L. The interaction between WDR5 and MLL1 plays an essential role in regulation of the H3K4 methyltransferase activity of MLL1 and targeting this interaction using small molecules may represent an attractive therapeutic strategy. In this study, we have defined the essential elements in MLL1 required for its high-affinity binding to WDR5. Our data showed that the minimal elements crucial for high-affinity binding of MLL1 to WDR5 are -CO-ARA-NH- motif and two intramolecular hydrogen bonds that stabilize the conformation of this motif. Two 3-mer peptides, Ac-ARA-NH(2) and Ac-ART-NH(2), were designed based upon MLL1 and H3 sequences and achieved K(i) values of 120 and 20 nM to WDR5, respectively. Our study provides a concrete basis for the design of potent peptidomimetics and nonpeptidic compounds to inhibit MLL1 activity by targeting the MLL1 and WDR5 interaction.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Karatas H,Townsend EC,Bernard D,Dou Y,Wang S

doi

10.1021/jm100139b

subject

Has Abstract

pub_date

2010-07-22 00:00:00

pages

5179-85

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • 1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: novel AMPA receptor antagonists.

    abstract：:Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. Th...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm960506l

    authors： Chimirri A,De Sarro G,De Sarro A,Gitto R,Grasso S,Quartarone S,Zappalà M,Giusti P,Libri V,Constanti A,Chapman AG

    更新日期：1997-04-11 00:00:00

  • Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).

    abstract：:The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in v...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00743

    authors： Rew Y,Du X,Eksterowicz J,Zhou H,Jahchan N,Zhu L,Yan X,Kawai H,McGee LR,Medina JC,Huang T,Chen C,Zavorotinskaya T,Sutimantanapi D,Waszczuk J,Jackson E,Huang E,Ye Q,Fantin VR,Sun D

    更新日期：2018-09-13 00:00:00

  • Synthesis and biological evaluation of analogues of Pro-Leu-Gly-NH2 modified at the leucyl residue.

    abstract：:A series of analogues of Pro-Leu-Gly-NH2 (PLG) in which the leucine residue has been replaced with the aliphatic amino acids L-isoleucine, L-2-aminohexanoic acid (Ahx), L-2-aminopentanoic acid, and L-2-aminobutanoic acid and the aromatic amino acids L-phenylalanine, L-phenylglycine, L- and D-2-amino-4-phenylbutanoic a...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00168a045

    authors： Johnson RL,Bontems RJ,Yang KE,Mishra RK

    更新日期：1990-06-01 00:00:00

  • Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

    abstract：:In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable f...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00447

    authors： Pemberton N,Mogemark M,Arlbrandt S,Bold P,Cox RJ,Gardelli C,Holden NS,Karabelas K,Karlsson J,Lever S,Li X,Lindmark H,Norberg M,Perry MWD,Petersen J,Rodrigo Blomqvist S,Thomas M,Tyrchan C,Westin Eriksson A,Zlatoidsky

    更新日期：2018-06-28 00:00:00

  • Synthesis and anti-tubulin activity of a 3'-(4-azidophenyl)-3'-dephenylpaclitaxel photoaffinity probe.

    abstract：:The synthesis and biological evaluation of a novel paclitaxel photoaffinity probe is described. The synthesis involved the preparation of an azide-containing C13 side chain through a Staudinger cycloaddition followed by a lipase-mediated kinetic resolution to obtain the azetidinone in 99% ee. Coupling of the enantiopu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030581d

    authors： Spletstoser JT,Flaherty PT,Himes RH,Georg GI

    更新日期：2004-12-16 00:00:00

  • Potential antiinflammatory compounds. 2. Acidic antiinflammatory 1,2-benzisoxazoles.

    abstract：:A number of 1,2-benzisoxazoles, substituted in the 3 position with 4-substituted phenyl groups and in the 5--7 positions with acetic and propionic acid residues, have been synthesized and tested in the rat carrageenan foot edema assay. Activity has been found in the 6- and 7-substituted acids. ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00198a026

    authors： Saunders JC,Williamson WR

    更新日期：1979-12-01 00:00:00

  • Structural basis for the interaction between tankyrase-2 and a potent Wnt-signaling inhibitor.

    abstract：:We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. The complex of TNKS2 with the potent inhibitor XAV939 provides insights into the molecular basis of the strong interaction and sugg...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100249w

    authors： Karlberg T,Markova N,Johansson I,Hammarström M,Schütz P,Weigelt J,Schüler H

    更新日期：2010-07-22 00:00:00

  • A one-pot synthesis and biological activity of ageladine A and analogues.

    abstract：:A one-pot synthesis of ageladine A and analogues is reported. The key Pictet-Spengler reaction between 2-aminohistamine and aryl aldehydes has been successfully utilized for the synthesis of the natural product and 14 analogues. These compounds were screened for their matrix metalloprotease (MMP) and kinase inhibition...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm200039m

    authors： Shengule SR,Loa-Kum-Cheung WL,Parish CR,Blairvacq M,Meijer L,Nakao Y,Karuso P

    更新日期：2011-04-14 00:00:00

  • Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design.

    abstract：:Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00057

    authors： Chen L,Zhuang C,Lu J,Jiang Y,Sheng C

    更新日期：2018-03-22 00:00:00

  • Fluorescent phenylpolyene analogues of the ether phospholipid edelfosine for the selective labeling of cancer cells.

    abstract：:Edelfosine (ET-18-OCH3), a synthetic antitumor ether lipid, is taken up by malignant but not by normal cells, triggering apoptosis in a large variety of human tumor cells. The synthesis of the first fluorescent edelfosine analogue (6), with apoptotic activity comparable to that of the parent drug, is described. Fluore...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm049808a

    authors： Quesada E,Delgado J,Gajate C,Mollinedo F,Acuña AU,Amat-Guerri F

    更新日期：2004-10-21 00:00:00

  • Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents.

    abstract：:A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl s...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.8b00986

    authors： Devine SM,Yong C,Amenuvegbe D,Aurelio L,Muthiah D,Pouton C,Callaghan R,Capuano B,Scammells PJ

    更新日期：2018-09-27 00:00:00

  • Further studies of the structure-activity relationships of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine. Synthesis and evaluation of 1-(2-benzo[b]thienyl)-N,N-dialkylcyclohexylamines at dopamine uptake and phencyclidine binding sites.

    abstract：:We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00077a011

    authors： He X,Raymon LP,Mattson MV,Eldefrawi ME,de Costa BR

    更新日期：1993-12-10 00:00:00

  • Phosphonothioate and fluoromethylene phosphonate analogues of cyclic phosphatidic acid: Novel antagonists of lysophosphatidic acid receptors.

    abstract：:Isoform-selective antagonists of the lysophosphatidic acid (LPA) G-protein coupled receptors (GPCRs) have important potential uses in cell biology and clinical applications. Novel phosphonothioate and fluoromethylene phosphonate analogues of carbacyclic phosphatidic acid (ccPA) were prepared by chemical synthesis. The...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060351+

    authors： Xu Y,Jiang G,Tsukahara R,Fujiwara Y,Tigyi G,Prestwich GD

    更新日期：2006-08-24 00:00:00

  • Improved scoring of ligand-protein interactions using OWFEG free energy grids.

    abstract：:A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000375v

    authors： Pearlman DA,Charifson PS

    更新日期：2001-02-15 00:00:00

  • Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators.

    abstract：:All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980303s

    authors： Kalgutkar AS,Kozak KR,Crews BC,Hochgesang GP Jr,Marnett LJ

    更新日期：1998-11-19 00:00:00

  • Synthesis of isosteres of p-amidinophenylpyruvic acid. Inhibitors of trypsin thrombin, and pancreatic kallikrein.

    abstract：:A series of amino acids, amidino acids, and amidino esters was synthesized and the compounds were evaluated for their inhibitory activity against bovine trypsin, bovine thrombin, and porcine pancreatic kallikrein and as anticoagulants. Among these compounds, ethyl 4-amidino-2-iodophenoxyacetate was found to be the mos...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00237a016

    authors： Geratz JD,Mar EC,Loeffler LJ,Fox LB

    更新日期：1975-03-01 00:00:00

  • Tyrosine kinase inhibitors. 2. Synthesis of 2,2'-dithiobis(1H-indole-3-alkanamides) and investigation of their inhibitory activity against epidermal growth factor receptor and pp60v-src protein tyrosine kinases.

    abstract：:A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkaonic acid) class of tyrosine kinase inhibitors have been prepared, by reaction of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisulfides formed. These amides were evaluat...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00031a009

    authors： Thompson AM,Fry DW,Kraker AJ,Denny WA

    更新日期：1994-03-04 00:00:00

  • Synthesis, NMDA receptor antagonist activity, and anticonvulsant action of 1-aminocyclobutanecarboxylic acid derivatives.

    abstract：:A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones wa...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00051a005

    authors： Gaoni Y,Chapman AG,Parvez N,Pook PC,Jane DE,Watkins JC

    更新日期：1994-12-09 00:00:00

  • N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.

    abstract：:Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped ve...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0108754

    authors： Fernandez AM,Van Derpoorten K,Dasnois L,Lebtahi K,Dubois V,Lobl TJ,Gangwar S,Oliyai C,Lewis ER,Shochat D,Trouet A

    更新日期：2001-10-25 00:00:00

  • p97: An Emerging Target for Cancer, Neurodegenerative Diseases, and Viral Infections.

    abstract：:The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a nu...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章,评审

    doi：10.1021/acs.jmedchem.9b01318

    authors： Huryn DM,Kornfilt DJP,Wipf P

    更新日期：2020-03-12 00:00:00

  • Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R).

    abstract：:The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.9b01071

    authors： Méndez M,Matter H,Defossa E,Kurz M,Lebreton S,Li Z,Lohmann M,Löhn M,Mors H,Podeschwa M,Rackelmann N,Riedel J,Safar P,Thorpe DS,Schäfer M,Weitz D,Breitschopf K

    更新日期：2020-03-12 00:00:00

  • Studies on anticoccidial agents. 10. Synthesis and anticoccidial activity of 5-nitronicotinamide and its analogues.

    abstract：:5-Nitronicotinamide (1) was prepared from 5-bromonicotinoyl chloride by treatment with ammonia and then oxidation with fuming H2SO4 and 30% H202. 2-Cholor-, 2-alkoxy-2-benzyloxy,2-phenoxy-,2-alkylamino-, and 2-benzylamino-5-nitronicatinamides were also prepared via 2-chloro-3-cyano-5-nitropyridine. 2-Methyl-5-nitronic...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00211a027

    authors： Morisawa Y,Kataoka M,Kitano N,Matsuzawa T

    更新日期：1977-01-01 00:00:00

  • Discovery of corticotropin releasing factor 2 receptor selective sauvagine analogues for treatment of skeletal muscle atrophy.

    abstract：:The corticotropin release factor 2 receptor (CRF2R) has many biological activities including modulation of the stress response. Recently, we have demonstrated that CRF2R activation functions to prevent skeletal muscle wasting resulting from a variety of physiological stimuli. Thus we are interested in identifying CRF2...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm049490m

    authors： Isfort RJ,Wang F,Tscheiner M,Donnelly E,Bauer MB,Lefever F,Hinkle RT,Mazur AW

    更新日期：2005-01-13 00:00:00

  • Synthesis of new linear guanidines and macrocyclic amidinourea derivatives endowed with high antifungal activity against Candida spp. and Aspergillus spp.

    abstract：:New linear and cyclic guanidines were synthesized and tested in vitro for their antifungal activity toward clinically relevant strains of Candida species, in comparison to fluconazole. Macrocyclic compounds showed a minimum inhibitory concentration in the micromolar range and a biological activity profile in some case...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm900760k

    authors： Manetti F,Castagnolo D,Raffi F,Zizzari AT,Rajamäki S,D'Arezzo S,Visca P,Cona A,Fracasso ME,Doria D,Posteraro B,Sanguinetti M,Fadda G,Botta M

    更新日期：2009-12-10 00:00:00

  • Bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins for breast tumor imaging and radiotherapy: synthesis and receptor binding affinity.

    abstract：:Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. We describe the synthesis and PR binding affinities of a series of bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins, some of which, when appropriately radiolabeled, are pot...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060348q

    authors： Zhou D,Carlson KE,Katzenellenbogen JA,Welch MJ

    更新日期：2006-07-27 00:00:00

  • Nitro seco analogues of the duocarmycins containing sulfonate leaving groups as hypoxia-activated prodrugs for cancer therapy.

    abstract：:The synthesis of 19 (5-nitro-2,3-dihydro-1H-benzo[e]indol-1-yl)methyl sulfonate prodrugs containing sulfonate leaving groups and 7-substituted electron-withdrawing groups is reported. These were designed to undergo hypoxia-selective metabolism to form potent DNA minor groove-alkylating agents. Analogues 17 and 24, con...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm201717y

    authors： Stevenson RJ,Denny WA,Tercel M,Pruijn FB,Ashoorzadeh A

    更新日期：2012-03-22 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

  • A novel approach for the virtual screening and rational design of anticancer compounds.

    abstract：:A topological substructural approach to molecular design (TOSS-MODE) has been introduced for the selection and design of anticancer compounds. A quantitative model that discriminates anticancer compounds from the inactive ones in a training series was obtained. This model permits the correct classification of 91.43% o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm991172d

    authors： Estrada E,Uriarte E,Montero A,Teijeira M,Santana L,De Clercq E

    更新日期：2000-05-18 00:00:00

  • Pseudodipeptide inhibitors of protein farnesyltransferase.

    abstract：:A series of pseudodipeptide amides are described that inhibit Ras protein farnesyltransferase (PFTase). These inhibitors are truncated versions of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation. In contrast to CAAX peptidomimetics previousl...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00020a010

    authors： deSolms SJ,Deana AA,Giuliani EA,Graham SL,Kohl NE,Mosser SD,Oliff AI,Pompliano DL,Rands E,Scholz TH

    更新日期：1995-09-29 00:00:00

  • Crystal, solution, and molecular modeling structural properties and muscarinic antagonist activity of azaprophen.

    abstract：:The structure of azaprophen, which was originally assigned by 1H NMR analysis, was confirmed by X-ray crystallography. A comparison of 13C NMR isotropic chemical shift data for azaprophen in the solid state and in CDCl3 and DMSO-d6 solution was used to correlate solution and solid-state conformation as determined by t...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00108a030

    authors： Carroll FI,Abraham P,Mascarella SW,Singh P,Moreland CG,Sankar SS,Kwon YW,Triggle DJ

    更新日期：1991-04-01 00:00:00