- TARGET PROTEIN EED DEGRADATION-INDUCING DEGRADUCER, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DISEASES RELATED TO EED, EZH2, OR PRC2, COMPRISING SAME AS ACTIVE INGREDIENT
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The present invention relates to a target protein degradation-inducing Degraducer, a preparation method thereof, and a pharmaceutical composition for preventing or treating diseases related to EED, EZH2, or PRC2 comprising same as an active ingredient. A novel compound represented by formula 1, according to the present invention is a Degraducer compound that induces degradation of a target protein, i.e., embryonic ectoderm development (EED) or polycomb repressive complex 2 (PRC2), utilizing cereblon E3 ubiquitin ligase, von Hippel-Lindau tumor suppressor (VHL) E3 ubiquitin ligase, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase, and cellular inhibitor of apoptosis protein 1 (cIAP) E3 ubiquitin ligase, wherein the compound has an aspect of remarkably achieving target protein degradation-inducing activity through a ubiquitin proteasome system (UPS), and therefore there is a useful effect in that it is possible to provide a pharmaceutical composition for preventing or treating diseases or conditions related to a target protein, and a functional health food composition for preventing or improving same, comprising said compound as an active ingredient.
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Paragraph 0166-0167
(2021/12/23)
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- Synthesis and characterization of a new two photon excitable acid sphingomyelinase FRET probe
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Recently, FRET probes for acid sphingomyelinase (ASM) have enabled the observation of enzyme activity in intact cells for the first time. Here we present an ASM FRET probe specifically optimized for 2-photon excitation. To facilitate probe characterization and comparison to the previous probe, we mixed the two intact probes with defined amounts of the probes' ceramide cleavage products and mounted them on lipid beads. Directly excited NBD FRET acceptor fluorescene proved to be a useful means of reference and showed that the new probe is brighter, albeit only moderately, than the previous one. The new probe was then used to detect inhibition by various ASM inhibitors microscopically for the first time. Also in cells, directly excited acceptor fluorescence proved to be a useful parameter in addition to FRET to visualize inhibition of ASM.
- Mohamed, Zain H.,Rhein, Cosima,Schmid, Benjamin,Tripal, Philipp,Kornhuber, Johannes,Arenz, Christoph
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- Ozone-Mediated Amine Oxidation and Beyond: A Solvent-Free, Flow-Chemistry Approach
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Ozone is a powerful oxidant, most commonly used for oxidation of alkenes to carbonyls. The synthetic utility of other ozone-mediated reactions is hindered by its high reactivity and propensity to overoxidize organic molecules, including most solvents. This challenge can largely be mitigated by adsorbing both substrate and ozone onto silica gel, providing a solvent-free oxidation method. In this manuscript, a flow-based packed bed reactor approach is described that provides exceptional control of reaction temperature and time to achieve improved control and chemoselectivity over this challenging transformation. A powerful method to oxidize primary amines into nitroalkanes is achieved. Examples of pyridine, C-H bond, and arene oxidations are also demonstrated, confirming the system is generalizable to diverse ozone-mediated processes.
- Skrotzki, Eric A.,Vandavasi, Jaya Kishore,Newman, Stephen G.
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p. 14169 - 14176
(2021/06/30)
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- Identification of New Small-Molecule Inducers of Estrogen-related Receptor α (ERRα) Degradation
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A series of (E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-cyanoacrylamide derivatives were designed and synthesized as new estrogen-related receptor α (ERRα) degraders based on the proteolysis targeting chimera (PROTAC) concept. One of the representative compounds 6c is capable of specifically degrading ERRα protein by >80% at a relatively low concentration of 30 nM, becoming one of the most potent and selective ERRα degraders to date. Compound 6c could be utilized as a new powerful research tool for further biological investigation of ERRα.
- Peng, Lijie,Zhang, Zhensheng,Lei, Chong,Li, Shan,Zhang, Zhang,Ren, Xiaomei,Chang, Yu,Zhang, Yan,Xu, Yong,Ding, Ke
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supporting information
p. 767 - 772
(2019/05/08)
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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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supporting information
p. 1037 - 1041
(2019/06/27)
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- DEGRADATION OF PROTEIN KINASES BY CONJUGATION OF PROTEIN KINASE INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
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The present application provides bifunctional compounds of Formula (I), or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.
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Page/Page column 116-117
(2018/05/27)
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- MAYTANSINOID DERIVATIVES, CONJUGATES THEREOF, AND METHODS OF USE
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Provided herein are maytansinoid derivatives, conjugates thereof, and methods of treating or preventing proliferative diseases with the same.
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Paragraph 0566; 0568
(2016/10/27)
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- BIOLOGICALLY ACTIVE MOLECULE CONJUGATES, REAGENTS AND METHODS OF MANUFACTURE, AND THERAPEUTIC USES
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The present disclosure relates to conjugates comprising biologically active molecules linked to a multimeric antigen-binding compound or a multimeric immunoglobulin via a linker. The disclosure further provides reagents and methods of manufacturing the conjugates and the linkers. The disclosure also provides compositions comprising the conjugates, methods of modifying abnormal cell growth and methods of treatment using the conjugates or the compositions.
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Paragraph 00236; 00238
(2015/12/30)
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- QUINONE-MASKED PROBES AS LABELING REAGENTS FOR CELL UPTAKE MEASUREMENTS
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Provided are labeling reagents and methods of using the reagents for cell uptake measurements. The labeling reagents can be quinone- masked probes including fluorophores and/or luminophores.
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Paragraph 00273
(2015/09/23)
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- Carboxyalkyl peptoid PNAs: Synthesis and hybridization properties
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Nγ-Carboxyalkyl modified peptide nucleic acids (PNAs), containing the four canonical nucleobases, were prepared via solid-phase oligomerization. The inserted peptoid monomers 1 and 2 were constructed through simple synthetic procedures, utilizi
- De Cola, Chiara,Manicardi, Alex,Corradini, Roberto,Izzo, Irene,De Riccardis, Francesco
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experimental part
p. 499 - 506
(2012/01/14)
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- Irinotecan Immunoassay
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Novel conjugates of the pharmaceutically active metabolite of irinotecan and novel immunogens derived from this pharmaceutically active metabolite and monoclonal antibodies generated by these immunogens which are useful in immunoassays for the quantification and monitoring of the pharmaceutically active metabolite of irinotecan in biological fluids.
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- IRINOTECAN IMMUNOASSAY
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Novel conjugates of the pharmaceutically active metabolite of irinotecan and novel immunogens derived from this pharmaceutically active metabolite and monoclonal antibodies generated by these immunogens which are useful in immunoassays for the quantificat
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Page/Page column 28; 31
(2011/06/26)
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- SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS FOR THE TREATMENT OF CARDIOVASCULAR DISEASE
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The present application relates to novel substituted bicyclic heteroaryl compounds, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or proph
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Page/Page column 31
(2010/11/03)
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- Synthesis and self-association properties of flexible guanidiniocarbonylpyrrole-carboxylate zwitterions in DMSO: Intra- versus intermolecular ion pairing
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(Chemical Equation Presented) We have synthesized a new class of flexible zwitterions 6a-e, in which a carboxylate is linked via an alkyl chain with variable length (one to five methylene groups) to a guanidiniocarbonylpyrrole cation. The self-association properties of these zwitterions were determined by NMR dilution studies in DMSO and by ESI-MS experiments. The stability and hence also the size of the aggregates formed via self-assembly is critically dependent on the length and therefore flexibility of the spacer. Whereas the smallest zwitterion 6a forms large aggregates already at low concentrations, the more flexible zwitterions only form small oligomers (6b) or dimers (6c-e) at much larger concentrations. The differences between the five zwitterions can be explained based on the different extent of intramolecular ion pairing within the monomers. Any intramolecular ion pairing, which becomes possible with increasing linker length, stabilizes the monomer and therefore destabilizes any oligomer.
- Schmuck, Carsten,Rehm, Thomas,Geiger, Lars,Schaefer, Mathias
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p. 6162 - 6170
(2008/02/10)
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- Synthesis of camptothecin melantotransferrin (p97) conjugate through a carbamate bond
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Through its 20-hydroxy group and a carbamate bond, 20(S)-camptothecin (1) is chemically linked to melanotransferrin (p97). The key step to modify the steric hindered hydroxy group of camptothecin is achieved by using triphosgene/DMAP in DMF and immediately reacting with tert-butyl 6-aminohexanoate (8). The novel camptothecin conjugate 4 is a potential agent for chemotherapy of brain tumor.
- Chen, Qingqi,Gabathuler, Reinhard
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p. 2415 - 2424
(2007/10/03)
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- Development of an enzyme-linked immunosorbent assay for the detection of the organophosphorus insecticide acephate
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A competitive indirect enzyme-linked immunosorbent assay (ciELISA) for the organophosphorus insecticide acephate, O,S-dimethyl acetylphosphoramidothioate, was developed using a polyclonal antibody. Five different haptens mimicking the analyte were synthesized and conjugated with the carrier proteins bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH) by the N-hydroxysuccinimide active ester and diazotization methods. Polyclonal antibodies raised against hapten - KLH conjugates in rabbits and hapten - BSA conjugates as coating antigens were screened and selected for the assay in the homologous and heterologous ELISA systems. The effects of various assay conditions such as detergent, organic solvents, pH, and preincubation of the mixture of the polyclonal antibody and the analyte on the sensitivity were evaluated. The IC50 value for acephate was 25 ng/mL in an optimized heterologous system using hapten-4 - BSA as a coating antigen and a polyclonal antibody no. 8377 against hapten-1 - KLH, showing the detection range of 5-140 ng/mL and the lowest detection limit of 2 ng/mL. The cross-reactivities of the structurally related organophosphorus insecticides, including the major metabolite of the analyte, methamidophos, were less than 1%. Recoveries from the analyte-fortified tap water, mulberry leaves, and lettuce samples in the assay were in the range of 72-121% by simple extraction, concentration, and dilution. These results indicate that the ELISA could be a convenient and supplemental analytical tool for monitoring acephate residues in environmental and agricultural samples.
- Lee, Jae Koo,Ahn, Ki Chang,Stoutamire, Donald W.,Gee, Shirley J.,Hammock, Bruce D.
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p. 3695 - 3703
(2007/10/03)
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- Building Units for N-Backbone Cyclic Peptides. 3. Synthesis of Protected Nα-(ω-Aminoalkyl)amino Acids and Nα-(ω-Carboxyalkyl)amino Acids
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An improved synthesis of a family of amino acids that contain ω-aminoalkyl groups and of a new family containing ω-carboxyalkyl groups linked to the α-amine is described. The synthesis was performed by alkylation of suitably monoprotected alkylenediamines and protected ω-amino acids with triflates of α-hydroxy acid esters. The reaction proceeded with inversion of configuration yielding optically pure products. The Nα-(ω-aminoalkyl)amino acids and Nα-(ω-carboxyalkyl)amino acids were orthogonally protected to allow their incorporation into peptides by solid-phase peptide synthesis (SPPS) methodology.
- Muller, Dan,Zeltser, Irena,Bitan, Gal,Gilon, Chaim
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p. 411 - 416
(2007/10/03)
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- A Conceptual Approach to the Synthesis of Bifunctional EDTA Analogs: EDTA-Extended Polyamides
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A conceptual approach to the synthesis of ε-carboxyl and ε-amino polyamide-linked EDTAs is proposed (Scheme 1), starting from ε-carboxy vicinal diamine blocked by Cbz or Boc groups (A, Scheme 1), followed by extension along the chain to form polyamides with ε-carboxy groups (A2, A3,..., An) or amine groups (B1, B2,..., Bn).The An series can be converted to acidic EDTAs (AEn series) or basic EDTAs (BEn series).This depends on the selection of the protecting groups to offer exclusive protection of the amine and acid functions.The choice of the protecting groups (three categories a-c in Scheme 1) provides an exclusive synthetic methodology.This is further exploited for conversion of acidic polyamide-linked EDTA (AEn) to either acidic or basic EDTA homologs (see Scheme 2).Scheme 4 proposes metnodology for synthesis of terminally blocked bis-EDTA polyamides.
- Kahana, N.,Arad-Yellin, R.,Warshawsky, A.
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p. 4832 - 4837
(2007/10/02)
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