94 results about "Ubiquitin ligase binding" patented technology

The invention provides a DHODH polypeptide degradation agent and application of the DHODH polypeptide degradation agent in preparation of drugs for preventing and / or treating DHODH-mediated diseases, and belongs to the technical field of biological medicines. The invention provides a DHODH polypeptide degradation agent. The DHODH polypeptide degradation agent comprises a cell-penetrating peptide, a DHODH binding peptide, a linker and an E3 ubiquitin ligase VHL binding peptide which are sequentially connected from an N terminal to a C terminal. The DHODH polypeptide degradation agent provided by the invention can be efficiently combined with DHODH protein, and has a good anti-tumor effect on the cellular level and the animal level. The compound has a good application prospect in preparation of drugs for preventing and treating DHODH-mediated diseases, overcomes the defects that existing drugs for treating DHODH-related diseases are single in variety and insufficient in curative effect, and has important significance.

Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, 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 aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

The invention relates to the technical field of biological medicine, in particular to an mRNA vaccine based on a protein degradation technology. The mRNA vaccine comprises an mRNA system and a lipid nanoparticle. The mRNA system refers to two mRNAs which can respectively encode an antigen-docking module and a recognition module-E3 ubiquitin ligase binding domain, the E3 ubiquitin ligase binding domain recruits an E3 ubiquitin ligase complex, the antigen is ubiquitinated and degraded into a peptide fragment by utilizing specific binding between the recognition module and the docking module, the peptide fragment is recognized by an MHC-I complex, and the E3 ubiquitin ligase binding domain is used for identifying the MHC-I complex. Then, the body immunity is activated, and the anti-tumor effect is realized. Besides, the invention provides a universal mRNA vaccine, that is, theoretically, different diseases can be treated only by replacing antigens in an mRNA system, the research and development time of the vaccine is greatly shortened, the research and development cost is reduced, a new thought is provided for tumor treatment, and the mRNA vaccine has a huge application prospect.

The invention provides a DHODH polypeptide degradation agent and application of the DHODH polypeptide degradation agent in preparation of drugs for preventing and / or treating DHODH-mediated diseases, and belongs to the technical field of biological medicines. The invention provides a DHODH polypeptide degradation agent. The DHODH polypeptide degradation agent comprises a cell-penetrating peptide, a DHODH binding peptide, a linker and an E3 ubiquitin ligase VHL binding peptide which are sequentially connected from an N terminal to a C terminal. The DHODH polypeptide degradation agent provided by the invention can be efficiently combined with DHODH protein, and has a good anti-tumor effect on the cellular level and the animal level. The compound has a good application prospect in preparation of drugs for preventing and treating DHODH-mediated diseases, overcomes the defects that existing drugs for treating DHODH-related diseases are single in variety and insufficient in curative effect, and has important significance.

The present disclosure relates to bifunctional compounds, which find utility as modulators of Protein Arginine N-Methyl Transferase 5 (PRMT5) in MTAP deleted / low expressing cells. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds the PRMT5-MTA complex, such that the PRMT5 protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of PRMT5 protein, as well as methods for their preparation and use. Specifically, the present invention describes compounds of Formula (I) and pharmaceutically acceptable salts, hydrates and solvates, as well as methods for their preparation and use

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

1. A compound of formula (I): [MCL-1 ligand site]-[linker]-[ligase ligand site] (I), or a salt, solvate, hydrate, isomer, or prodrug thereof, wherein [MCL-1 ligand site] is a compound of formula (A), or [MCL-1 ligand site] is a compound of formula (A1), (A2), (A3), or (A4), and use thereof in the treatment of cancer. [Formula 1] JPEG2025540970000791.jpg126170

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

Provided here are IRE1 degrader compounds comprising a protein target moiety covalently attached by a linker to an E3 ubiquitin ligase-binding moiety. Also provided are intermediate compositions for the preparation of IRE 1 degrader compounds and methods of treating diseases and disorders such as cancer with the IRE1 degrader compounds.

Compounds and pharmaceutical compositions useful to treat cancer (e.g., lymphoma), neurodegenerative diseases, and autoimmune disorders include (1) a first nucleic acid sequence capable of binding to a transcription factor, for example, a signal transducer and activator of transcription (STAT) factor, such as STAT3, (2) a second nucleic acid sequence capable of binding a Toll-like receptor protein, for example, a CpG oligodeoxynucleotide, and (3) a ubiquitin ligase binding compound capable of binding a ubiquitin ligase protein, for example, a compound that is capable of binding a cereblon protein, such as lenalidomide, pomalidomide, or thalidomide.

This invention provides pharmaceutical protein degraders and E3 ubiquitin ligase binders for therapeutic applications as described further herein.

The present application relates to a PROTAC construction based on E3 ubiquitin ligase ZER1 and target protein DVL2 and its application in heart failure treatment. In particular, the present application provides a proteolysis targeting chimera (PROTAC) complex comprising an E3 ubiquitin ligase binding ligand moiety and a target protein binding ligand moiety connected by a linker, wherein the E3 ubiquitin ligase binding ligand is a ZER1 binding ligand, and the target protein binding ligand is a DVL2 binding ligand. The PROTAC molecule in the present application targets DVL2 ubiquitination degradation by recruiting E3 ubiquitin ligase ZER1 to regulate the CaMKII / HDAC4 / MEF2C signaling axis, thereby reducing pathological cardiac hypertrophy and intervening the progression of heart failure, and providing a new therapeutic target for treating cardiac hypertrophy and heart failure caused by pressure overload.

Provided is a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein the bifunctional compound is represented by Formula (I):wherein:ABM is an androgen receptor binding moiety;-L- is a linking moiety; andCLM is a cereblon E3 ubiquitin ligase binding moiety represented by Formula (II)-1:wherein one end of the -L- is covalently joined to Q3, Q4, Q5 or Q6; and the other end of the -L- is covalently joined to the ABM. Also provided are a pharmaceutical composition comprising the bifunctional compound and a method for treating an androgen receptor related disease by administering the bifunctional compound.

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

Disclosed are proteolysis-targeting chimeric molecules (PROTACs) that induce degradation of IDO protein. The disclosed PROTACs typically include a first targeting moiety that binds to IDO (Miro). The first targeting moiety typically is linked via a bond or a linker (L) to a second targeting moiety that binds to an E3 ubiquitin ligase (ME3). As such, the disclosed PROTACS may be described as having a formula MIDO-L-ME3 or ME3-L-MIDO.

The invention relates to a compound which is a Proteolysis Targeting Chimera (PROTAC) or a pharmaceutically acceptable salt thereof, wherein the PROTAC has the structure (AA) wherein U is an E3 ubiquitin ligase binding moiety, LINK is a moiety that covalently links M and U, and M is an MLLT1 and / or MLLT3 binder of formula (I) wherein Z1, Z2, Y1, Y2, Y3, R1, R2, R8, X, L and Hy are as defined herein, and either R8 is a bond to LINK, or M is bonded to LINK via a C or N atom within group R8 or ring Hy such that a hydrogen atom on the C or N atom within group R8 or ring Hy is replaced with a bond to LINK. The compounds are useful in the treatment of cancer.

Disclosed herein is a molecule, or a pharmaceutically acceptable salt thereof, that has a formula M1DO1-L-ME3, M1DO1 is a moiety that binds to IDO1, L is a linker covalently attaching M1DO1 and ME3, and ME3 is a moiety that binds to an E3 ubiquitin ligase. Disclosed herein are also the uses of the molecule, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same, in a method of treating cancer in a subject in need thereof.

Described herein are CDK9 degraders that include a CDK9 binding moiety, such as AT7519 or VIP152, conjugated to a E3 ubiquitin ligase binding moiety, such as thalidomide, lenalidomide, or pomalidomide. These degraders can induce the ubiquitination of CDK9 and promote its degradation in cells. The linker covalently tethering the CDK9 binding moiety to the E3 ubiquitin ligase binding moiety can be selected to tune the solubility profile and potency of the degrader. Accordingly, the present disclosure provides compounds, compositions, kits, uses, and methods for the treatment of cancer (e.g., blood cancers such as acute myeloid leukemia or acute lymphoblastic leukemia).

Bifunctional compounds, which find utility as modulators of androgen receptor (AR), 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 AR, 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 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 present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

The application provides a DHODH polypeptide degrading agent and application thereof in preparation of a medicine for preventing and / or treating a DHODH-mediated disease, and belongs to the technical field of biological medicine.The application provides a DHODH polypeptide degrading agent, which comprises, from N-terminal to C-terminal, a cell-penetrating peptide, a DHODH binding peptide, a linker and an E3 ubiquitin ligase VHL binding peptide connected in sequence.The DHODH polypeptide degrading agent provided by the application can efficiently bind to DHODH protein, and has good antitumor effect at the cellular level and the animal level.The DHODH polypeptide degrading agent has a good application prospect in preparation of a medicine for preventing and treating a DHODH-mediated disease, and can make up for the defects of single type and insufficient efficacy of existing medicines for treating DHODH-related diseases, and has important significance.

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and a E3 ubiquitin ligase binding moiety, and associated methods of use.

The present disclosure relates to methods of co-administering PROTAC (proteolysis targeting chimera) compounds that can promote ubiquitination and degradation of a target protein. The present disclosure also relates to antibody drug conjugates of PROTAC compounds Also disclosed herein are pharmaceutical compositions that can include a compound of Formula (V), the use and preparation thereof.

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use.

The invention discloses a targeted receptor ubiquitination induced antibody fusion protein coupling drug and application thereof, and the antibody fusion protein coupling drug comprises: (a) an antibody fusion protein, which comprises an antibody structural domain capable of binding to a tumor-associated antigen receptor; the membrane binding type E3 ubiquitin ligase binding module is fused with the antibody structural domain, and the E3 ubiquitin ligase binding module is an RSPO2 FU (F109A) structural domain; wherein the antibody fusion protein can be simultaneously combined with a tumor associated antigen receptor and a membrane binding type E3 ubiquitin ligase RNF43 and / or ZNRF3; and (b) a cytotoxic small molecule drug coupled with the antibody fusion protein. According to the invention, by introducing a membrane binding type E3 ubiquitin ligase binding module, the antibody can promote ubiquitination modification and lysosomal pathway degradation while binding to a tumor-associated antigen receptor, so that the internalization efficiency and tumor killing activity of the antibody-conjugated drug are significantly improved.

The present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X1 is CH or N; p is 0, 1 or 2; wherein: each R1 is a substituent on any C atom and is independently selected from the group consisting of F, Cl, C1-3 alkyl and C1-3 alkoxy wherein the C1-3 alkyl and C1-3 alkoxy may be independently optionally substituted by one or more F; rN is selected from H and Me; n is 0, 1 or 2; m is 0 or 1; q1 is CH or N; q2 is CH or N when neither n nor m is 0; when both n and m are 0, Q2 is CH; when n is 0 or 1, Q3 is CH; when n is 2 and Q2 is N, Q3 is CH; when n is 2 and Q2 is CH, Q3 is CH or O; r2a and R2b are substituents on the same or different C atoms other than at Q1 or Q2, each independently selected from H, F and C1-3 alkyl, or R2a and R2b together form a-(CH2) r-group wherein r is 1, 2 or 3; q4 is a single bond or-NR4C (= O); r4 is H or Me; 0, 1, or 2 of Y1, Y2, Y3, Y4, and Y5 is N, otherwise C; each R3 is a substituent on any C atom at Y1, Y2, Y3, Y4 and Y5 and is independently selected from the group consisting of F, Cl, CN, C1-3 alkyl and C1-3 alkoxy wherein the C1-3 alkyl and C1-3 alkoxy may be independently optionally substituted by one or more F; q is 0, 1 or 2; wherein the linker is attached to any available C atom at Y4 and Y5; the linker is a saturated or partially or fully unsaturated framework comprising a C atom and an H atom and at least one heteroatom, wherein the framework has a length of 5 to 26 atoms connecting the endpoints'a 'and'b' and between'a 'and'b'; wherein the framework may comprise one or more linear and / or branched chains and / or rings and are optionally substituted by one or more F on any available C atom; and W is an E3 ubiquitin ligase cerebron binding agent unit.

The present invention relates to a bifunctional compound, a preparation method therefor, and a use thereof, wherein the bifunctional compound comprises an E3 ubiquitin ligase-binding moiety; a target protein-binding moiety that binds to an androgen receptor; and a linking moiety that links the E3 ubiquitin ligase-binding moiety and the target protein-binding moiety. The bifunctional compound of the present application allows the androgen receptor to be positioned adjacent to the ubiquitin ligase, so as to achieve the degradation or inhibition of the androgen receptor.