- Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling
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Cell-based screening is a powerful approach to identify novel chemical modulators and biological components of relevant biological processes. The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis, and its deregulation plays a crucial role in carcinogenesis. Therefore, the identification of new pathway members and regulators is of significant interest. By means of a cell-based assay monitoring Wnt signaling we identified the pyrrolocoumarin Pyrcoumin as inhibitor of canonical Wnt signaling. Target identification and validation revealed that Pyrcoumin is a competitive inhibitor of dCTP pyrophosphatase 1 (dCTPP1). We demonstrate a yet unknown interaction of dCTPP1 with ubiquitin carboxyl-terminal hydrolase (USP7) that is counteracted by dCTPP1 inhibitors. These findings indicate that dCTPP1 plays a role in regulation of Wnt/β-catenin signaling most likely through a direct interaction with USP7.
- Friese, Alexandra,Kapoor, Shobhna,Schneidewind, Tabea,Vidadala, Srinivasa Rao,Sardana, Juhi,Brause, Alexandra,F?rster, Tim,Bischoff, Matthias,Wagner, Jessica,Janning, Petra,Ziegler, Slava,Waldmann, Herbert
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- Photo-accelerated "click" reaction between diarylsydnones and ring-strained alkynes for bioorthogonal ligation
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We constructed a library of diarylsydnone (DASyd) candidates in search of a photoclickable reaction toward alkynes, enabling an ultra-accelerated reactivity, while suppressing the background cycloaddition in the dark. The in vitro and in vivo protein labe
- Zhang, Xiaocui,Wu, Xueting,Jiang, Shichao,Gao, Jingshuo,Yao, Zhuojun,Deng, Jiajie,Zhang, Linmeng,Yu, Zhipeng
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- A sulfur tripod glycoconjugate that releases a high-affinity copper chelator in hepatocytes
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Released in the cell: Three N-acetylgalactosamine units, which recognize the asialoglycoprotein receptor, were tethered through disulfide bonds to the three coordinating thiol functions of a sulfur tripod ligand that has a high affinity for CuI (see scheme). The resulting glycoconjugate can be considered as a prodrug, because after uptake by hepatic cells the intracellular reducing glutathione (GSH) releases the high-affinity intracellular Cu I chelator. Copyright
- Pujol, Ana?s M.,Cuillel, Martine,Jullien, Anne-Solène,Lebrun, Colette,Cassio, Doris,Mintz, Elisabeth,Gateau, Christelle,Delangle, Pascale
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- Design and Synthesis of Fluorescent Methylphenidate Analogues for a FRET-Based Assay of Synapsin III Binding
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We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxic
- Casiraghi, Andrea,Longhena, Francesca,Straniero, Valentina,Faustini, Gaia,Newman, Amy H.,Bellucci, Arianna,Valoti, Ermanno
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- Covalent Protein Labeling by Enzymatic Phosphocholination
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We present a new protein labeling method based on the covalent enzymatic phosphocholination of a specific octapeptide amino acid sequence in intact proteins. The bacterial enzyme AnkX from Legionella pneumophila has been established to transfer functional phosphocholine moieties from synthetically produced CDP-choline derivatives to N-termini, C-termini, and internal loop regions in proteins of interest. Furthermore, the covalent modification can be hydrolytically removed by the action of the Legionella enzyme Lem3. Only a short peptide sequence (eight amino acids) is required for efficient protein labeling and a small linker group (PEG-phosphocholine) is introduced to attach the conjugated cargo.
- Heller, Katharina,Ochtrop, Philipp,Albers, Michael F.,Zauner, Florian B.,Itzen, Aymelt,Hedberg, Christian
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- Site-selective protein modification: Via disulfide rebridging for fast tetrazine/ trans -cyclooctene bioconjugation
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An inverse electron demand Diels-Alder reaction between tetrazine and trans-cyclooctene (TCO) holds great promise for protein modification and manipulation. Herein, we report the design and synthesis of a tetrazine-based disulfide rebridging reagent, which allows the site-selective installation of a tetrazine group into disulfide-containing peptides and proteins such as the hormone somatostatin (SST) and the antigen binding fragment (Fab) of human immunoglobulin G (IgG). The fast and efficient conjugation of the tetrazine modified proteins with three different TCO-containing substrates to form a set of bioconjugates in a site-selective manner was successfully demonstrated for the first time. Homogeneous, well-defined bioconjugates were obtained underlining the great potential of our method for fast bioconjugation in emerging protein therapeutics. The formed bioconjugates were stable against glutathione and in serum, and they maintained their secondary structure. With this work, we broaden the scope of tetrazine chemistry for site-selective protein modification to prepare well-defined SST and Fab conjugates with preserved structures and good stability under biologically relevant conditions.
- Chudasama, Vijay,Kuan, Seah Ling,Nogueira, Jo?o C. F.,Raabe, Marco,Weil, Tanja,Xu, Lujuan,Zegota, Maksymilian M.
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- CYP1B1 enzyme targeting probe precursor for radioactivity F labeling
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The invention discloses a CYP1B1 enzyme targeting probe precursor for radioactivity F labeling. The probe precursor comprises an affinity ligand capable of being combined with CYP1B1 enzyme, a chelating group capable of being used for 18F rapid label
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Paragraph 0027-0029
(2021/02/10)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001046-001048
(2020/06/19)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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- A MedChem toolbox for cereblon-directed PROTACs
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A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.
- Steinebach, Christian,Sosi?, Izidor,Lindner, Stefanie,Bricelj, Ale?a,Kohl, Franziska,Ng, Yuen Lam Dora,Monschke, Marius,Wagner, Karl G.,Kr?nke, Jan,Gütschow, Michael
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p. 1037 - 1041
(2019/06/27)
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- Alkyl indole-based cannabinoid type 2 receptor tools: Exploration of linker and fluorophore attachment
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Cannabinoid type 2 (CB2) receptor continues to emerge as a promising drug target for many diseases and conditions. New tools for studying CB2 receptor are required to further inform how this receptor functions in healthy and diseased states. The alkyl indole scaffold is a well-recognised ligand for cannabinoid receptors, and in this study the indole C5-7 positions were explored for linker and fluorophore attachment. A new high affinity, CB2 receptor selective inverse agonist was identified (16b) along with a general trend of C5-substituted indoles acting as agonists versus C7-substituted indoles acting as inverse agonists. The indole C7 position was found to be the most tolerant to linker extension and resulted in a high affinity inverse agonist with a medium length linker (19). Although a high affinity fluorescent ligand for CB2 receptor was not identified in this study, the indole C7 position shows great promise for fluorophore or probe attachment.
- Cooper, Anna G.,MacDonald, Christa,Glass, Michelle,Hook, Sarah,Tyndall, Joel D.A.,Vernall, Andrea J.
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p. 770 - 789
(2018/02/10)
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- Polypeptide, protein PEG modifier synthesis method
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The present invention discloses a synthesis route and an operation method of a peptide and protein pegylation agent, wherein the pegylation agent is used for polypeptides and drug structure modification, the raw materials of the method are cheap, and the amount of the polyethylene glycol can be defined.
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- PHENYL TETRAHYDROISOQUINOLINE COMPOUND SUBSTITUTED WITH HETEROARYL
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The present invention provides a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof which has an excellent NHE3 inhibitory effect: ????????[Formula 15]?????A-Y [1] wherein A represents a structure represented b
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Paragraph 0343; 0344
(2017/06/29)
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- MONOFUNCTIONAL INTERMEDIATES FOR LIGAND-DEPENDENT TARGET PROTEIN DEGRADATION
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The present disclosure provides compounds represented by Formula I: and the salts or solvates thereof, wherein X, L, Y, and B are as defined in the specification. Compounds having Formula I are immunomodulators and/or monofunctional synthetic intermediates that can be used to prepare small-molecule drug conjugates.
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Paragraph 0859-0860
(2017/11/04)
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- MDM2-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The description relates to MDM2 binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Paragraph 0376; 0383
(2017/01/31)
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- MODIFIED THERAPEUTIC AGENTS AND COMPOSITIONS THEREOF
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Methods and compositions are provided for extending the half-life of a therapeutic agent. One half-life extending moieties may be attached to a therapeutic agent, thereby extending the half life of the therapeutic agent. The modified therapeutic agents comprising a half-life extending moieties attached to a therapeutic agent may be used to treat a disease or condition in a subject in need thereof.
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Paragraph 0314
(2016/10/04)
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- TETRACYCLIC ANTHRAQUINONE DERIVATIVES
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Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, W, n are defined as in the present application.
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- Tetracyclic Anthraquinone Derivatives
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Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, W, n are defined as in the present application.
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- MODIFIED THERAPEUTIC AGENTS AND COMPOSITIONS THEREOF
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Methods and compositions are provided for extending the half-life of a therapeutic agent. One or more half-life extending moieties may be attached to a therapeutic agent, thereby extending the half life of the therapeutic agent. The modified therapeutic agents (mTAs) comprising one or more half-life extending moieties attached to a therapeutic agent may be used to treat a disease or condition in a subject in need thereof.
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Paragraph 0466; 0468
(2015/03/28)
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- Bioorthogonal approach to identify unsuspected drug targets in live cells
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A proteomics method to pull down secondary drug targets from live cells is described. The drug of interest is modified with trans-cyclooctene (TCO) and incubated with live cells. Upon cell lysis, the modified drug bound to the protein is pulled down using magnetic beads decorated with a cleavable tetrazine-modified linker. Samples are then run on an SDS-PAGE gel and isolated bands are submitted for mass spectrometry analysis to identify drug targets. Copyright
- Yang, Katherine S.,Budin, Ghyslain,Tassa, Carlos,Kister, Olivier,Weissleder, Ralph
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supporting information
p. 10593 - 10597
(2013/10/21)
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- Synthesis of Patent Blue derivatized hydrophilic dendrons dedicated to sentinel node detection in breast cancer
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In the last decade, methods for the precise localization of sentinel lymph node (SLN) have drawn tremendous attention by oncology surgeons and researchers in the field of medical diagnosis. The accurate identification and characterization of lymph nodes by imaging has important therapeutic and prognostic significance in patients with newly diagnosed cancers. The SLN is the first lymph node that receives lymphatic drainage from the site of a primary tumor. Two biocompatible dendronized phosphonates, one bearing a Patent Blue (PB VF) dye at its periphery, where synthesized. Indeed, such a blue dye is currently injected to label the lymph node system for its per-operative detection. Therefore, developing chemistry of Patent Blue VF to optimize early diagnosis is of great current interest.
- Kueny-Stotz, Marie,Mamlouk-Chaouachi, Hind,Felder-Flesch, Delphine
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scheme or table
p. 2906 - 2909
(2011/06/21)
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- Zinc(II)cyclen-peptide conjugates interacting with the weak effector binding state of Ras
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Zinc(II)cyclen-peptide hybrid compounds and bis-zinc(II)cyclen complexes are prepared as potential binders of the guanine nucleotide binding protein Ras, an important molecular switch in cellular signal transduction. The design of the compounds is based on the previous observation that zinc(II)cyclen complexes could serve as lead compounds for inhibitors of Ras-effector interaction and thus be able to interrupt Ras induced signal transduction. Zinc(II)cyclen selectively stabilizes conformational state 1 of active Ras, a conformational state with drastically decreased affinity to effector proteins like Raf-kinase. To achieve higher binding affinities of such Ras-Raf interaction inhibitors, zinc(II)cyclen conjugates with short peptides, derived from the sequence of the Ras-activator SOS, were prepared by solid phase synthesis protocols. Dinuclear bis-zinc(II)cyclen complexes were obtained from alkyne-azide cycloaddition reactions. NMR investigations of the prepared compounds revealed that the peptide conjugates do not lead to an increase in Ras binding affinity of the metal complex-peptide conjugates. The dinuclear zinc complexes lead to an immediate precipitation of the protein prohibiting spectroscopic investigations of their binding.
- Schmidt, Florian,Rosnizeck, Ina C.,Spoerner, Michael,Kalbitzer, Hans Robert,K?nig, Burkhard
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- Functional virus-based polymer-protein nanoparticles by atom transfer radical polymerization
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Viruses and virus-like particles (VLPs) are useful tools in biomedical research. Their defined structural attributes make them attractive platforms for engineered interactions over large molecular surface areas. In this report, we describe the use of VLPs as multivalent macroinitiators for atom transfer radical polymerization. The introduction of chemically reactive monomers during polymerization provides a robust platform for post-synthetic modification via the copper-catalyzed azide-alkyne cycloaddition reaction. These results provide the basis to construct nanoparticle delivery vehicles and imaging agents using protein-polymer conjugates.
- Pokorski, Jonathan K.,Breitenkamp, Kurt,Liepold, Lars O.,Qazi, Shefah,Finn
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p. 9242 - 9245
(2011/08/06)
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- Effect of multivalency on the performance of enantioselective separation media for chiral HPLC prepared by linking multiple selectors to a porous polymer support via aliphatic dendrons
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Chiral stationary phases (CSPs) containing L-proline indananilide chiral selectors attached through a multivalent dendritic linker to monodisperse macroporous poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) beads have been prepared using two different approaches. The convergent method involves the preparation of ligands in solution and their subsequent attachment to the support. The divergent approach is based on the stepwise "on-bead" formation of the linker using methods that are typical of solid-phase synthesis. While the convergent CSPs feature well-defined ligands, their loading is relatively low. In contrast, the divergent technique affords CSPs with higher loading but with more limited control over precise ligand architecture. Excellent enantioselectivities characterized by separation factors of up to 31 were achieved for the separation of racemic N-(3,5-dinitrobenzoyl)-α-amino acid alkyl amides with these new CSPs under normal-phase HPLC conditions.
- Ling, Frank H.,Lu, Victor,Svec, Frantisek,Frechet, Jean M. J.
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p. 1993 - 2002
(2007/10/03)
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- Synthesis of New Phospholipids Linked to Steroid-Hormone Derivatives Designed for Two-Dimensional Crystallization of Proteins
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The synthesis of phospholipids 1n-3n, rationally designed for two-dimensional crystallization of progesterone and estradiol receptors, is reported.The structure of theses lipids provides them with essential properties such as fluidity and stability when spread into monolayers at the air/H2O interface, affinity for the protein to be crystallized, and accessibility of the ligand under the lipid monolayer.
- Lebeau, Luc,Oudet, Pierre,Mioskowski, Charles
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p. 1697 - 1706
(2007/10/02)
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- Precursor to nucleic acid probe
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Nucleic acids may be labeled by intercalating the alkylating intercalation moiety of a labeling reagent into a partially double-stranded nucleic acid to form a complex and activating the complex to cause covalent bonding between the reagent and the nucleic acid. Preferably, the labeled nucleic acid is a hybridization probe for detecting nucleic acid sequences capable of hybridizing with a hybridizing region of the nucleic acid. Also preferably the label moiety is non-radioactive. The labeling reagent is of the formula: where A is an alkylating intercalation moiety, B is a divalent organic moiety of the formula: STR1 where Y is O, NH or N--CHO, x is a number from 1 to 4, y is a number from 2 to 4, and L is a monovalent label moiety, wherein B is exclusive of any portion of the intercalation and label moieties. Preferably A is a 4-methylene-substituted psoralen moiety, and most preferably A is a 4'-methylene-substituted-4,5', 8-trimethylpsoralen moiety and L is biotin. This patent application is a divisional application of copending U.S. Ser. No. 791,332 filed Oct. 25, 1985, now U.S. Pat. No. 4,617,261, which is a continuation-in-part application (CIP) of copending U.S. Ser. No. 683,263 filed Dec. 18, 1984, now U.S. Pat. No. 4,582,789 which is a CIP of copending U.S. Ser. No. 591,811 filed Mar. 21, 1984, now abandoned. This patent application is also related to copending U.S. application Ser. No. 791,323 filed Oct. 25, 1985.
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