106 results about "Proteolysis targeting chimera" patented technology

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 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 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.

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.

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.

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.

The present application provides a protein degradation targeting chimera molecule and application thereof, the protein degradation targeting chimera molecule has the structure shown in formula (I), the protein degradation targeting chimera molecule of the present application can significantly degrade IRAK kinase, which shows efficient, high selective IRAK4 and / or IRAK1 degradation effect, and can be used for treating or preventing diseases related to IRAK4 and / or IRAK1 activity.

Provided are cyanoquinoline targeted protein degradation molecules, methods of making and uses thereof. In particular, the application relates to compounds of general formula (I), methods of making the same, and pharmaceutical compositions containing the same, and uses thereof as androgen receptor targeted protein degradation chimeras, in the manufacture of medicaments for the treatment of diseases related to androgen receptor regulation, including prostate cancer, breast cancer, Kennedy's disease, wherein the substituents in general formula (I) are the same as defined in the specification.

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or a solvate thereof, and a pharmaceutical composition thereof and the use thereof in the treatment of c-Kit or PDGFRα-related diseases.

The invention relates to the field of biological medicine, and discloses a protein degradation targeting chimera (PROTAC) compound targeting 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) and medical application of the protein degradation targeting chimera (PROTAC) compound. The compound comprises a structural unit shown as a formula I, X is a 11 beta-HSD1 binding ligand, Y is a connecting chain, Z is an E3 ubiquitin ligase ligand, ubiquitination degradation of 11 beta-HSD1 can be induced, and therefore the function of the compound can be regulated and controlled at the protein level. Different from a traditional small-molecule inhibitor, the degradation agent can significantly reduce expression of 11 beta-HSD1 in cells and improve glucocorticoid signal abnormality, and shows a novel action mode at molecular and cellular levels. In diabetes, obesity, lipid metabolism disorder and related complication models, the compound can reduce blood sugar, improve insulin sensitivity, regulate blood fat and relieve inflammation, and shows a good treatment prospect. The half degradation concentration of a representative compound in vitro is about 1000 nM, and feasible degradation efficiency is achieved. The compound can be synthesized by Click chemistry and other methods, and can be prepared into a pharmaceutical composition for prevention and treatment of type II diabetes, metabolic syndrome, polycystic ovarian syndrome and other diseases, and a new strategy is provided for research and development of related drugs.

The present invention relates to certain compounds of Formula (I) that function as a proteolysis targeting chimera (PROTAC) against CCR2; wherein X, L, E3, ring A, integer a, Y, ring B, integer b and Z are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which CCR2 activity is implicated.

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.

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, e.g., to promote degradation of KRAS G12D and / or treat KRAS G12D-associated cancers. In an embodiment, the KRAS G12D PROTAC has the following structural formula:[KRAS G12Di]-L′-[Degron],or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., KRAS G12Di, L′, Degron) are as described herein.

A proteolysis targeting chimera is provided of Formula I:wherein: T includes a target binding moiety capable of binding to a target protein; L includes a linker moiety; and U includes a ubiquitin ligase-recruiting moiety capable of binding a ubiquitin ligase; wherein any of T, L, or U further includes a first stimulus-reactive moiety S1, wherein S1 is reactive to a first stimulus; and wherein any of T, L, or U further includes a second stimulus-reactive moiety S2, wherein S2 is reactive to a second stimulus, wherein the second stimulus is different than the first stimulus.

The present disclosure relates generally to PROTAC (Protein Degradation Targeting Chimera) compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds in the treatment of various diseases and conditions.

The invention relates to the technical field of biological medicine, in particular to a 11 beta-HSD1 targeting protein degradation targeting chimera as well as a preparation method and application thereof. The protein degradation targeting chimera is a compound as shown in a formula I or a pharmaceutically acceptable salt, in the formula I, X is a ligand of 11 beta-HSD1 protein, Z is a ligand of E3 ligase, and Y is a connecting part of X and Z; the protein degradation targeting chimera can effectively reduce the protein level and improve cognitive disorder of AD model mice and depressive disorder of chronic stress model mice.

The invention belongs to the technical field of medicine. The invention discloses an FGFR protein degradation targeting chimera, a pharmaceutical composition taking the FGFR protein degradation targeting chimera as an active ingredient, and application of the FGFR protein degradation targeting chimera in preparation of drugs for preventing or treating FGFR kinase mediated diseases or symptoms. Specifically, the invention relates to a compound shown as a formula (I), pharmaceutically acceptable salts, stereoisomers or solvates thereof, and a pharmaceutical composition containing the compound, and R1, R2, R3, L and X are described in the specification.

The invention provides a bifunctional protein degradation agent for directly targeting proteasome, and a preparation method and application thereof. The bifunctional protein degradation agent comprises a POI ligand for specifically binding to a to-be-degraded target protein related to a disease; the proteasome ligand is used for specifically binding a protein degradation tool proteasome; and a linker chain moiety linking the proteasome ligand to the POI ligand. Specifically, according to the degradation technology, degradation is achieved by directly collecting POIs near intracellular proteasomes. The invention establishes a novel targeted protein degradation technology platform, and provides a method for preparing the protein degradation agent at the same time. The invention also has the advantages that the compound molecule not only recruits POI to proteasome, but also can improve the hydrolytic activity of the proteasome and enhance the degradation efficiency of the POI. And the proteasome is highly expressed in all cells, and tissue specificity does not exist, so that the direct targeting proteasome degradation agent in the technology can be widely applied.

The present invention relates to a protein degradation targeting chimera (protac) compound binding to BRD4 protein, which can bind to and decompose BRD4 protein, and thus can be effectively used for treating or preventing diseases associated with BRD4 protein. The compound disclosed by the invention has an excellent anti-cancer effect, and can show a treatment effect on BRD4 related diseases by inducing decomposition of BRD4 protein.

The invention relates to the technical field of protein degradation targeting chimeras, in particular to an FAK protein degradation targeting chimera degradation agent and a preparation method thereof. The FAK protein degradation targeting chimera degradation agent is selected from a compound represented by the following structural formula: in the formula, X represents O or ethynyl, R represents C1-C3 unsubstituted alkyl, and n is 3-12. The FAK protein degradation targeted chimera degradation agent can effectively reduce the FAK protein level, and then has a good treatment effect on FAK protein mediated diseases.

The invention discloses a protein degradation targeting chimera for an EGFR-VHL system. The protein degradation targeting chimera comprises an EGFR binding molecule and a VHL binding molecule, the EGFR binding molecule is any one of proteins as shown in SEQ ID NO.1 to SEQ ID NO.3; the VHL binding molecule is any one of proteins as shown in SEQ ID NO. 4 to 37. The invention also discloses application of the protein degradation targeting chimera in preparation of drugs targeting EGFR and VHL. The invention provides a set of complete calculation design framework, a diversified candidate binding protein library is generated, and finally three high-quality EGFR binding proteins and 34 high-quality VHL binding proteins are obtained and show excellent prediction evaluation indexes. The invention establishes a general framework which is preliminarily verified and is suitable for the rational design of the next generation of protein PROTAC, and lays a foundation for a targeted protein degradation treatment strategy of tumors and other diseases.