67 results about "Cereblon" patented technology

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI / SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and / or polybromo-1 (PB-1) protein via ubiquitination and / or degradation by compounds. The compounds are bifunctional molecules that link a cereblon-binding moiety to a ligand that binds SMARCA and / or PB1 proteins.

This document provides bifunctional compounds, one part of which (e.g., lenalidomide, thalidomide) is a binder of an E3 ubiquitin ligase (e.g., Cereblon) and the other part of which is a binder of a target protein (e.g., a kinase (e.g., CDK (e.g., CDK9 and / or CDK12))) to induce the degradation of the target protein CDK9 and / or CDK12. Pharmaceutical compositions comprising bifunctional compounds are also provided, as well as methods for treating and / or preventing diseases (e.g., proliferative diseases such as cancers (e.g., ovarian cancer, breast cancer, or prostate cancer)). Methods for inducing the degradation of target proteins (e.g., kinases (e.g., CDK (e.g., CDK9 and / or CDK12))) and methods for inducing apoptosis in biological samples or subjects by administering the bifunctional compounds or compositions described herein are also provided.

Certain Androgen receptor PROTAC (PROteolysis TArgeting Chimera) compounds contain a series of 2,4-dioxotetrahydropyrimidinyl derivatives that bind cereblon. The PROTAC compounds may be viewed as being comprised of an androgen receptor binding moieties, a linker and a cereblon binding moiety or degron. Medical uses of these PROTAC compounds are also disclosed.

The present disclosure relates to novel compounds that act as modulators of cereblon (CRBN). The compounds promote CRBN-mediated ubiquitination and proteasomal degradation of oncogenic proteins such as GSPT1 and MYC, thereby suppressing abnormal cell growth. Pharmaceutical compositions containing the compounds and methods of using the compositions for the treatment of cancers, particularly solid tumors, are also provided.

The present disclosure relates to a compound of Formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analogue, solvate, prodrug or polymorph thereof, and the use thereof. Further provided in the present disclosure are a pharmaceutical composition comprising, as an active ingredient, the compound of Formula (I) or a salt, enantiomer, diastereomer, isotopically enriched analogue, solvate, prodrug or polymorph thereof, and the use thereof. A series of compounds designed and synthesized in the present disclosure can effectively prevent and / or treat diseases or disorders associated with cereblon protein.

A compound of formula I or a stereoisomer, isotopic isomer, tautomer or pharmaceutically acceptable salt thereof: wherein a ligand that binds to Nef protein (NB) is covalently linked to a ligand that binds to E3 ligase cerebron (CB) via a linker (L).

Provided herein are targeting constructs for sustained transgene expression of inducible cell death systems that include degron mutants and cereblon mutants. Also provided are pharmaceutical compositions comprising the targeting constructs, and methods for use of the same. The methods of use include methods of inducing cell death in a cell, and methods of treating patients in need thereof.

Disclosed are compounds and salts thereof that bind to and modulate the activity of cereblon. In some embodiments, the binding and modulation of cereblon results in the degradation of IKAROS family zinc finger proteins (e.g., IKZF2). The compounds are represented by Formula I: TIFF2026502995000081.tif43170

To provide compounds that find utility as modulators of RapidlyAcceleratedFibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF; target proteins).SOLUTION: The present invention is directed to bifunctional compounds that contain a von Hippel-Lindau, cereblon, Inhibitorsof Apoptosis Proteins, or mousedouble-RAF ligand that binds to the respective E3 ubiquitin ligase at one end and a moiety that binds to the target proteins RAF at the other end, such that the target proteins are placed in proximity to the ubiquitin ligase to effect degradation (and minutehomolog2) of the target proteins. The present disclosure presents a wide range of pharmacological activities related to degradation / inhibition of target proteins.SELECTED DRAWING: None

The application discloses application of TRIM11 protein in preparation of a medicine for treating spinocerebellar ataxia 51. The application adopts an SCA51 specific cell model, and identifies, through a large number of screening experiments, that the TRIM11 protein has the function of significantly removing mutant THAP11 protein and aggregates thereof. Experimental data show that the mutant protein removal efficiency of the TRIM11 treatment group is significantly better than that of the control group. The application verifies the removal effect of TRIM11 on the SCA51 pathological protein from the two dimensions of protein expression level and subcellular localization through Western blotting quantitative analysis and immunofluorescence co-localization technology. The three-dimensional reconstruction image clearly shows that the mutant protein aggregates are significantly reduced. The application first establishes a complete research system from target discovery to mechanism analysis, and provides a new intervention strategy for precise treatment of SCA51.

Certain Androgen receptor PROTAC (PROteolysis TArgeting Chimera) compounds contain a series of 2,4-dioxotetrahydropyrimidinyl derivatives that bind cereblon. The PROTAC compounds may be viewed as being comprised of an androgen receptor binding moieties, a linker and a cereblon binding moiety or degron. Medical uses of these PROTAC compounds are also disclosed.

Bifunctional compounds, which find utility as modulators of non-receptor Leucine-rich repeat kinase 2 (LRRK2), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

To provide cereblon ligands and bifunctional compounds comprising the ligands.SOLUTION: The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the compounds, 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 disclosure. Specifically, the description provides compounds which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein, so 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 activity consistent with the degradation / inhibition of targeted polypeptides of nearly any type.SELECTED DRAWING: None

This invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.

The present disclosure provides a compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof and uses thereof. The present disclosure also provides pharmaceutical compositions comprising, as an active ingredient, the compound of Formula (I) or salts, enantiomers, stereoisomers, solvates, or polymorphs thereof and uses thereof. The series of compounds designed and synthesized in the present disclosure can effectively prevent and / or treat diseases or disorders associated with the cereblon protein.

The description relates to cereblon E3 ligase 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 disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon 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.

The present invention provides a method for evaluating the efficacy of a drug in the treatment of a disease or disorder, comprising determining whether the drug causes or inhibits the recruitment and / or ubiquitination and / or degradation of argininosuccinate synthase 1 (ASS1). [Solution] A method for identifying candidate compounds, comprising: (a) obtaining a test compound having the ability to bind to cereblon (CRBN); (b) Contacting the test compound with CRBN in the presence of argininosuccinate synthase 1 (ASS1); (c) Assaying for the direct or indirect recruitment and / or ubiquitination and / or degradation of ASS1; and (d) Classify the test compound as a candidate compound if a reduction, decrease, or substantially absence of direct or indirect recruitment and / or ubiquitination and / or degradation of ASS1 is detected. This provides a method that includes [something].

This invention provides Degron compounds which bind to cereblon which is a component of the E3 ubiquitin ligase. The Degrons provided herein can be used to modulate the activity of cereblon either alone or as covalently linked to a Tail. Alternatively, the Degron can be linked to a Targeting Ligand which binds to a Target Protein for protein degradation.

Provided are the use of cereblon (CRBN) as a biomarker for diagnosis of hepatocellular carcinoma and novel monoclonal antibodies specific to CRBN. More specifically, provided are a composition and a kit for diagnosing or predicting the prognosis of hepatocellular carcinoma by using CRBN as a biomarker for diagnosis of hepatocellular carcinoma, an information providing method for diagnosing or predicting the prognosis of hepatocellular carcinoma, two novel monoclonal antibodies binding specifically to CRBN, and hybridoma cells producing the same. The expression level difference of CRBN protein allows patients with hepatocellular carcinoma to be diagnosed early and indicates better predictive capabilities than the presence or absence of microvascular invasion, which was an important factor in predicting a prognosis of hepatocellular carcinoma in prior art, and thus can be expected to be used as a diagnostic marker to diagnose hepatocellular carcinoma and to evaluate a prognosis after hepatic resection.

In one aspect, the disclosure relates to substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindolin-5-yl)arylsulfo namide analogs that useful as modulators of cereblon (CRBN) activity, methods of making same, pharmaceutical compositions comprising same, and methods of treating various clinical conditions and disorders using same, e.g., a disorder of uncontrolled cellular proliferation, such as a cancer, which may be associated with cereblon protein dysfunction and / or a GSPT1 dysfunction. In various further aspects, the disclosed compounds can selectively modulate the degradation of GSPT1 protein, i.e., the disclosed compounds can act as GSPT1 degraders. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Bifunctional compounds, which find utility as modulators of non-receptor tyrosine kinase 2 (TYK2), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds TYK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

The application provides preparation and application of a PROTAC degrading agent, and relates to the field of medicines.The ganoderic acid A-PROTAC compound with degrading activity provided by the application takes ganoderic acid A as raw material, retains the structural skeleton of ganoderic acid A, and is connected with E3 ubiquitin ligase Cereblon (CRBN) or VHL ligand by using different lengths of fatty chains or polyethylene glycol (PEG) chains to obtain ganoderic acid A derivatives GAA C1-C10 and V1-V10.The ganoderic acid A derivative with novel antitumor effect and the like is synthesized by a simple synthesis method.The ganoderic acid A derivative has the structure shown in the following general formula I.

The present disclosure relates to salts and solid forms of compounds that bind to celebron, thereby modulating the activity of celebron, and methods of using the salts and solid forms of the compounds to treat various IKZF2 mediated diseases or disorders, such as proliferative diseases or disorders and / or cancers.

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.

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI / SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and / or polybromo-1 (PB-1) protein via ubiqitination and / or degradation by compounds. The compounds are bifunctional molecules that link a cereblon-binding moiety to a ligand that binds SMARCA and / or PB1 proteins.

The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

In one aspect, the disclosure relates to compounds of Formula (I) comprising a cereblon degrader precursor comprising an acyclic glutarimide moiety. In certain embodiments, the acyclic glutarimide moiety7 converts to a glutarimide moiety7 upon exposure to a stimulus. In certain embodiments, the compound of Formula (I) comprises at least one selected from the group consisting of a Proteolysis Targeting Chimera (PROTAC). degrader antibody conjugate (DAC), and / or Immunomodulatory Imide Drug (IMiD). In another aspect, the disclosure relates to methods of use of the compounds described herein for the treatment of a disease or disorder, including but not limited to cancer.

The present invention discloses novel compounds that bind to cereblon, and methods of using the same. The compounds are represented by the following formulas (I), (IIa)-(IIc), (III) and (IV): [Formula 1] JPEG2024501537000138.jpg73121JPEG2024501537000139.jpg87121

The present disclosure relates to novel compounds that act as modulators of cereblon (CRBN). The compounds promote CRBN-mediated ubiquitination and proteasomal degradation of oncogenic proteins such as GSPT1 and MYC, thereby suppressing abnormal cell growth. Pharmaceutical compositions containing the compounds and methods of using the compositions for the treatment of cancers, particularly solid tumors, are also provided.