156 results about "Proteolysis targeting chimera" patented technology

Provided herein are KRAS proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS PROTACs, and methods of making and using the KRAS PROTACs, e.g., to promote degradation of KRAS and / or treat KRAS-associated cancers. In an embodiment, the KRAS PROTAC has the structural formula (I) or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.

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 invention discloses a cationic polymer-based proteolysis targeting chimera as well as preparation and application thereof, and belongs to the fields of targeting protein degradation and nanotechnology. According to the chimera, a cationic polymer is used as a connecting arm to connect a target protein ligand and an E3 ubiquitin ligase ligand to form a ternary complex, so that efficient degradation of target protein is realized. By adjusting the ligand proportion, chimeras with different degradation efficiencies can be synthesized, and accurate regulation and control are realized. The pH-responsive nano-drug obtained by hydrolyzing the targeting chimera by using the targeting protein can respond to an acidic tumor microenvironment, specifically release the chimera, and improve the targeting property and the treatment effect of the drug. Compared with the traditional PROTACs, the compound has higher bioavailability and tumor permeation effect; the preparation method of the nano-drug is simple and easy to implement, provides possibility for preparation of high-performance nano-drugs, shows potential in preparation of anti-tumor cell drugs, provides new thoughts and methods for tumor treatment, and has important clinical application value.

The present application provides compounds that are proteolysis targeting chimeras containing a celastrol-based ubiquitin ligase targeting moiety. Methods of using these compounds for treating various diseases, such as neurodegenerative diseases and cancer, are also provided.

Provided are a cyanoquinoline-targeting protein degradation molecule, a preparation method therefor and a use thereof. Particularly, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition comprising the compound, and a use of the compound as a protein degradation targeting chimera of an androgen receptor in preparation of medicaments for treating related diseases (including prostate cancer, breast cancer, and spinal and bulbar muscular atrophy) controlled by the androgen receptor, wherein the definitions of the substituents in general formula (I) are the same as those in the description.

Described herein are programmable DNA proteolytic target chimera complexes that can be used both for the direct treatment of cancer by inhibiting biochemical pathways that are overexpressed in cancer cells, and for the indirect treatment of cancer by recruiting the E3 ligase complex to engage with a protein of interest or a mutant thereof and initiating proteolysis. Also described herein are methods of using the complexes in the treatment of cancer, as well as compositions comprising the complexes.

The invention discloses a structural analysis system and a modeling method for a protein degradation targeting chimera compound, and belongs to the field of computer-aided drug molecule design. The structural analysis system comprises a chimera component analysis module, a chimera induced complex component analysis module and a chimera linker length distribution analysis module, so that automatic structural splitting and analysis of the protein degradation targeted chimera drug are realized; through protein-protein docking, conformation search, conformation fusion and optimization, conformation clustering and conformation scoring and sorting, efficient and accurate structure modeling is realized. According to the method, automatic component splitting and structure analysis can be carried out, so that a potential drug molecule binding mode is comprehensively explored, the trial and error cost and time of traditional drug structure analysis are remarkably reduced, the design efficiency and success rate of a protein degradation targeting chimera are remarkably improved, and through automatic parameter optimization, the design efficiency of the protein degradation targeting chimera is greatly improved. And the high efficiency and reliability of the structure modeling process are ensured.

The invention discloses a novel HIF-2 alpha proteolysis targeting chimera 1 as well as a preparation method and application thereof, the structural formula 1 of the novel HIF-2 alpha proteolysis targeting chimera 1 is shown in the specification, and the obtained novel HIF-2 alpha proteolysis targeting chimera 1 has good proliferation inhibition activity on kidney cancer 786-O cells. The novel HIF-2alpha protein hydrolysis targeting chimera designed by the invention is novel in structure, few in preparation route process steps, easy to obtain raw materials, suitable for industrial production and good in application value.

The invention discloses a preparation method and application of targeted protein degradation nanoparticles wrapped by liposome vesicles. The preparation method comprises the following steps: blending a protein degradation targeting chimera based on polydimethyldiguanide with hyaluronic acid, and forming polyprotein degradation targeting chimera nanoparticles through an electrostatic adsorption effect; and blending the liposome vesicles with the polyprotein degradation targeting chimera nanoparticles, and carrying out co-extrusion to obtain the targeting protein degradation nanoparticles wrapped by the liposome vesicles. The targeting protein degradation nano-particles wrapped by the liposome vesicles can overcome the hook effect of the protein degradation targeting chimera in tumor cells and achieve long circulation of the protein degradation targeting chimera in a living body, the in-vivo utilization rate of the protein degradation targeting chimera can be increased to the maximum extent, and the anti-tumor effect is enhanced.

The invention provides a protein degradation targeting chimera based on G-quadruplex RNA (Ribonucleic Acid) as well as a preparation method and application of the protein degradation targeting chimera. The structural general formula of the protein degradation targeting chimera is G-L-E, wherein G is G quadruplex RNA specifically combined with mammal fragile X hypophrenia protein (FMRP), E is a ligand of micromolecule E3 ubiquitination ligase, and L is a connecting arm between the G quadruplex RNA and the ligand of the micromolecule E3 ubiquitination ligase. The protein degradation targeting chimera provided by the invention has the advantages that the stability in an in-vivo environment and the capability of entering cells are greatly improved, and the protein degradation targeting chimera also has the capabilities of efficiently degrading FMRP and changing a secretion mode of cancer cells, so that a lot of convenience is provided for the development of nucleic acid PROTAC drugs.

Described herein are nucleic acid complexes which act as spatially activatable PROTACS which can be configured to optimally target a protein of interest with an E3 ligase. The nucleic acid complexes involve double-stranded DNA, XNAs, DNA / RNA hybrids, and double-stranded RNA.

To provide PROteolytic TArgeting Chimeras (PROTACs) capable of inactivating a G-protein coupled estrogen receptor (GPER).SOLUTION: A molecule comprising a G-protein coupled estrogen receptor (GPER) ligand coupled to a linker coupled to an E3 ubiquitin ligase ligand and methods of using the molecule are provided. In one embodiment, the GPER ligand is estradiol and the E3 ubiquitin ligase ligand is (S,R,S)-AHPC.SELECTED DRAWING: Figure 1

The present application relates to a proteolysis targeting chimera compound represented by formula (A) for degrading IRAK4 and a preparation method therefor, a pharmaceutical composition comprising said compound, and a use of the pharmaceutical composition for treating diseases, disorders or conditions associated with the kinase protein IRAK4.

The invention discloses a degradation agent based on benzimidazole fused covalent warheads as well as a preparation method and application of the degradation agent, and relates to the technical field of drug development. The structural formula of the degradation agent based on the benzimidazole fused covalent warhead is shown in the specification, wherein, is phenyl or substituted phenyl; r is methyl or tertiary butyl; the structure is selected from one of the following structures:,,,,,,,,, and; and a connection site is represented. According to the invention, a series of degradation agents based on benzimidazole fused covalent warheads are obtained by utilizing the modular design of a benzimidazole guiding group and an acrylate covalent warhead and then connecting with a BRD4 protein inhibitor JQ1 through a connexon. The degradation agent based on the benzimidazole fused covalent warhead can target the BRD4 protein and efficiently degrade the BRD4 protein. Therefore, targeted degradation of the BRD4 protein is realized while a protein degradation targeted chimera molecular library is enriched.

The invention relates to a difunctional chimera heterocyclic compound for targeted degradation of an androgen receptor and application of the difunctional chimera heterocyclic compound, and particularly provides a compound shown in a formula (I), or an isotope compound of the compound, or an optical isomer of the compound, or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound, or a prodrug of the compound, or a solvate of the compound, aRB is an androgen receptor recognition / combination part, L is a linking part, and U is a ubiquitin protease recognition / combination part; the three parts are connected through chemical bonds. The compound provided by the invention can degrade androgen receptors in prostate cancer cells in a targeted manner and inhibit proliferation of the prostate cancer cells, and also shows good metabolic stability and pharmacokinetic properties. The compound provided by the invention has a good application prospect in preparation of a protein degradation targeting chimera of an androgen receptor and in preparation of drugs for treating related diseases (including prostatic cancer, breast cancer and Kenildie disease) regulated and controlled by the androgen receptor. # imgabs0 #

The invention discloses a proteolysis targeting chimera and a preparation method thereof, and relates to the technical field of medicine preparation, the key points of the technical scheme are as follows: the proteolysis targeting chimera comprises RD1, RD2, RD3, RD4, RD5, RD6, RD7, RD8, RD9, RD10, RD11, RD12, RD13 and RD14, and the structure of the proteolysis targeting chimera is composed of a general structure (warhead R1 of RNF4), a VHL ligand or CRBN ligand and a linker; the structure of warhead R1 of RNF4 is as follows: # imgabs0 #, the structure of VHL ligand is as follows: # imgabs1 #, and the structure of CRBN ligand is as follows: # imgabs2 #

This invention relates to the field of nanomedicine delivery systems, specifically to an ultrasound-enhanced synergistic immunotherapy drug delivery system, its preparation method, and its applications. The ultrasound-enhanced synergistic immunotherapy drug delivery system includes a lipid shell and a fluorocarbon gas encapsulated within the lipid shell. The lipid shell is made from cancer cell membranes and a lipid membrane formed from synthetic phospholipids. The lipid shell integrates a protein degradation-targeting chimera for degrading PD-L1. This invention combines targeted drug delivery, PD-L1 targeted degradation, and ultrasound enhancement technology to construct an integrated synergistic immunotherapy drug delivery system. Through multi-mechanism synergistic action, it overcomes the bottlenecks of existing PROTAC delivery systems, achieving a highly efficient anti-tumor immune response. This technical solution solves the technical problems of limited tumor tissue penetration and cellular uptake efficiency of PROTAC degrading agents targeting PD-L1, resulting in unsatisfactory delivery effects and promising prospects for widespread application.

Provided herein are KRAS G12D proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS G12D PROTACs, and methods of making and using the KRAS G12D PROTACs, for example, to promote degradation of KRAS G12D and / or to treat cancers associated with KRAS G12D. KRAS G12D PROTAC has the structural formula: [KRAS G12Di]-L '-[Deron], or a pharmaceutically acceptable salt thereof, where KRAS G12Di is a KRAS G12D binding moiety, L' is a linker, and Deron is a selebron binding moiety. Preferably the compound is a compound of formula (VII). # imgabs0 #

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.

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.

Disclosed are bifunctional compounds (degraders) comprising a [Targeting ligand]-[Linker]-[Degron] adduct, the targeting ligand comprising a substituted pyridine compound, the bifunctional compounds targeting the epigenetic writer protein deoxyribonucleic acid methyltransferase 1, which is responsible for the maintenance of DNA methylation during cell proliferation, for degradation. Also disclosed are pharmaceutical compositions containing the compounds and methods of using the compounds to treat diseases and disorders characterized or mediated by aberrant DNMT1 activity.

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.

The invention belongs to the technical field of drug synthesis, and provides an EGC-based glutamate dehydrogenase degradation agent which comprises a structural general formula I, II or III. A series of conjugates of EGC and a protein degradation targeting chimera are synthesized to achieve the effect of intracellular GDH protein degradation, and GDH protein degradation can prevent degradation of a large amount of glutamic acid, so that toxicity to nerve cells caused by generation of a large amount of ammonia is prevented; and a new strategy is provided for treatment of rare diseases of the high insulin-hyperamminemia syndrome and treatment of other diseases related to high expression of GDH. In order to improve the biological activity of a GDH inhibitor, the invention provides a series of degradation agents based on a PROTAC technology, namely EGCG and EGC derivatives, the degradation agents comprise protein degradation targeting chimera molecules, and GDH protein is more effectively degraded by utilizing an intracellular ubiquitin proteasome system.

The present invention relates to a monospecific or bispecific antibody, or an antibody fragment or fusion protein thereof, capable of binding to the VHL ligand VH032 (or derivative thereof) degrading moiety (degradation determinant) of a proteolytic targeting chimera (PROTAC), and optionally to a target protein. The invention also relates to complexes (PAX) of such antibodies, or antibody fragments or fusion proteins thereof, with PROTACS, as well as methods for their production, and their respective medical and non-medical uses.

Provided herein are KRAS proteolytic targeting chimeras (PROTACs), compositions comprising the KRAS PROTACs, and methods of making and using the KRAS PROTACs, for example, to promote degradation of KRAS and / or to treat KRAS-related cancers. In embodiments, KRAS PROTAC has the structural formula: or a pharmaceutically acceptable salt thereof, where the values of the variables (e.g., ring A, X4, Y, R2, R3, R4, L ', Detron) are as described herein.

The invention belongs to the field of pharmacy, and relates to a protein degradation targeting chimera (PROTAC) taking PD-L1 as a target spot and medical application thereof. The protein degradation targeting chimera is a compound composed of a target protein ligand, an E3 ligase ligand and a linker and a pharmaceutically acceptable salt of the compound, the specific structure of the compound is as shown in a formula I, and substituent groups are described in the specification in detail. A Western blot experiment (Western Blot) shows that the compound disclosed by the invention can be used for degrading the PD-L1 protein in a targeted manner.

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.

This invention provides novel small molecule non-ubiquitin proteolysis targeting chimera NuTAC, which degrades any selected proteins by directly tethering to the proteasome, processes for the preparation thereof, and its uses in medicine. This invention particularly provides NuTAC molecules with a binder of the proteasomal substrate receptor Rpn13 and a binder of the target protein PD-L1 or BRD4 to induce degradation of target proteins and suppress tumor growth. Also provided are an Rpn13 binder as well as an inhibitor RPI-5, which additionally induces phosphorylation of Rpn13, Src-3 and FBXO2, and another Rpn13 binder NuL1 that does not induce phosphorylation of above proteins. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating and / or preventing diseases (e. g., cancers), and methods of developing reagents to deplete cellular proteins.

Disclosed is a bifunctional compound (degradation agent) comprising a [targeting ligand]-[linker]-[degrader] adduct, the targeting ligand comprising a substituted pyridine compound, the bifunctional compound targeting an epigenetic writing protein desoxyribonucleic acid methyltransferase 1 responsible for maintaining DNA methylation during cell proliferation, for degradation. Also disclosed are pharmaceutical compositions containing the compounds and methods of using the compounds in the treatment of diseases and disorders characterized or mediated by aberrant DNMT1 activity.

The present disclosure relates to protein degradation targeting chimera (PROTAC) molecules, further to BRM selective degradation agent compounds, and specifically provides compounds of formula (I) or pharmaceutically acceptable salts thereof, the compounds having the substituents and structural characteristics described herein. Also described are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of said compound or a pharmaceutically acceptable salt thereof in medicine.