- A Buchwald–Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3-Ligase PROTACs**
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A palladium-catalysed Buchwald–Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.
- Borrows, Rachel E. A.,Diène, Coura R.,Fairley, Gary,Fallan, Charlene,Fillery, Shaun M.,Hayhow, Thomas G.,Scott, James S.,Watson, David W.
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Read Online
- PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases
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Glycogen synthase kinase 3β (GSK-3β) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC50 values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3β. Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3β is mediated by the ubiquitin-proteasome system (UPS). In addition, PG21 protects against glutamate-induced cell death in HT-22 cells. As the first PROTAC example to degrade GSK-3β protein, the present study has provided potential candidates for further investigation in the biological function of GSK-3β protein and its association with diseases.
- Jiang, Xueyang,Zhou, Junting,Wang, Yang,Liu, Xin,Xu, Kaiying,Xu, Jian,Feng, Feng,Sun, Haopeng
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supporting information
(2020/10/26)
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- COMPOUNDS MODULATING PROTEIN RECRUITMENT AND/OR DEGRADATION
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The invention provides cereblon binders for the degradation of proteins by the ubiquitin proteasome pathway for therapeutic applications.
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Paragraph 0454; 0455; 0477; 0480
(2021/06/26)
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- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
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The present invention relates to compounds of formula (I) useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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- MDM2 DEGRADERS AND USES THEREOF
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The present invention relates to compounds and methods useful for the modulation of mouse double minute 2 homolog ("MDM2") protein via ubiquitination and/or degradation by compounds according to the present invention.
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- Sulfur-containing compound based on glutaryl imide skeleton and application of compound
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The present disclosure relates to compound shown in a formula (I) or salts, solvates, isotope-enriched analogs, tautomers, polymorphs, stereoisomers, or mixtures of stereoisomers of the compound, andthe application thereof in the treatment of tumours. The present disclosure also provides tumor treatment application of the compound showed in a formula (I') or pharmaceutically acceptable salts, solvates, isotope-enriched analogs, tautomers, polymorphic substances, stereoisomers, or mixtures of stereoisomers of the compound.
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Paragraph 0321; 0324-0325
(2020/09/12)
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- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
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The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Paragraph 0615; 0618; 0619
(2020/05/21)
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- Isoindoline compound, and preparation method, pharmaceutical composition and application thereof
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The invention relates to a polysubstituted isoindoline compound represented by a general formula (I), and a preparation method, a pharmaceutical composition and an application thereof. Specifically, as a CRL4CRBNE3 ubiquitin ligase regulator with a novel structure, the polysubstituted isoindoline compound provided by the invention has stronger anti-tumor activity and an anti-tumor spectrum, and can be used for preparing medicines for treating diseases related to CRL4CRBNE3 ubiquitin ligase.
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Paragraph 0427; 0432-0434
(2020/04/17)
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- SMALL MOLECULE MDM2 PROTEIN DEGRADERS
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The present disclosure provides compounds represented by Formula I: wherein R1a, R1b, R2a, R2b, R3a, R3b, R4, A, L, X, Y, and Z are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat cancer or any other disease, condition, or disorder that is responsive to degradation of MDM2 protein.
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Paragraph 0256; 0259
(2020/04/29)
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- DIMERIC IMMUNO-MODULATORY COMPOUNDS AGAINST CEREBLON-BASED MECHANISMS
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Disclosed are small molecules against cereblon to enhance effector T cell function. Methods of making these molecules and methods of using them to treat various disease states are also disclosed.
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- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
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The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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- PROTEIN-TARGETING COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR THERAPEUTIC APPLICATIONS
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The present disclosure provides compounds, for example, a compound of Formula (I), that modulate a protein function and/or restore protein homeostasis. The disclosure provides a method of modulating a protein-mediated disease, disorder, condition, or response. Compositions, including in combination with other therapeutic agents, are provided.
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- Preparation method of target BTK protein degradation compound, and application of compound in treating autoimmune diseases and tumors
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The invention provides a compound, the compound is a compound represented by a formula I, and a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceuticallyacceptable salt and prodrug of the compound represented by the formula I. The compound has a strong degradation effect on wild-type BTK, has no inhibition or degradation effects on other targets suchas EGFR, ITK, TEC, and the like, and has an effect of specific targeted degradation of BTK proteins. The formula I is X-Y-Z.
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Paragraph 0240; 0243-0245
(2020/02/14)
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- Applications of targeted BTK degradation compound in treatment of autoimmune system diseases
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The invention discloses application of a targeted BTK degradation compound in treatment of autoimmune system diseases and in preparation of medicines which are used for treating or preventing autoimmune diseases. The targeted BTK degradation compound is a compound shown as formula I or a stereoisomer, a geometrical isomer, a tautomer, a nitric oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and the targeted BTK degradation compound has good treatment and prevention effects on the autoimmune diseases. X-Y-Z is as shown in formula I which is disclosed in the specification.
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Paragraph 0237-0239
(2020/03/12)
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- Compounds for targeted ubiquitination and degradation of GSK-3beta protein and application thereof
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The invention discloses compounds shown by a general formula (I) as shown in the specification. The compounds provided by the invention can effectively targetedly degrading GSK-3beta in vivo, and thetechnique can effectively reduce the dosage of administration and time of administration of pharmaceutical molecules to achieve the effect of prolonging PD.
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Paragraph 0048-0079; 0087-0089
(2019/09/17)
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- Compound capable of degrading PLK1 and BRD4 proteins, and applications thereof
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The invention relates to the field of medicinal chemistry, and concretely relates to a compound capable of performing target ubiquitination degradation of PLK1 and BRD4 proteins, a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound as an active component, and uses of the compound in the preparation of PLK1 and BRD4 protein inhibiting and degrading agents andin treatment and/or prevention of cancers as a therapeutic agent. The structure of the compound and the pharmaceutically acceptable salt thereof is shown in the description, and variables in the structure are as described in the claims and the description.
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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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- Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression
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The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
- Zhou, Bing,Hu, Jiantao,Xu, Fuming,Chen, Zhuo,Bai, Longchuan,Fernandez-Salas, Ester,Lin, Mei,Liu, Liu,Yang, Chao-Yie,Zhao, Yujun,McEachern, Donna,Przybranowski, Sally,Wen, Bo,Sun, Duxin,Wang, Shaomeng
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p. 462 - 481
(2018/02/07)
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- FUSED 1,4-DIAZEPINES AS BET PROTEIN DEGRADERS
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The present disclosure provides compounds represented by Formula I: I, and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1, R2a, R2b, R3, R4, Ar, L, X, Y, and B are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to degradation of BET bromodomains such as cancer.
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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 0867-0868
(2017/11/04)
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- AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION
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This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.
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Page/Page column 485-486
(2017/12/01)
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