56 results about "Proteolysis targeting chimera" patented technology

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.

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.

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.

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.

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.

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 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 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 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.

The present invention relates to proteolysis targeting chimera compounds of formula (I) having degradation and / or inhibitory activity on EGFR comprising a mutation thereof, and also relates to a pharmaceutical composition comprising same, and a preparation method therefor and the use thereof.

The invention discloses an E6 protein mutant serving as an E3 ubiquitin ligase ligand and an activating factor and application of the E6 protein mutant, and relates to the technical field of biological medicine. The amino acid sequence of the E6 protein mutant is as shown in SEQ ID NO. 1. According to the invention, E6 protein is modified to obtain an E6 protein mutant, and the E6 protein mutant is used as a novel E3 ubiquitin ligase ligand and an activating factor and is applied to construction of a protein degradation targeting chimera. Compared with the prior art, the invention provides a new tool for the PROTAC technology. The E6 protein mutant serving as an E3 ubiquitin ligase ligand and an activating factor can be combined with ubiquitin protein ligase UBE3A / E6AP in a targeted mode, and after the E6 protein mutant is combined with a target protein ligand of target protein, formed fusion protein can activate the ubiquitin protein ligase UBE3A / E6AP and efficiently degrade the target protein in a targeted mode.

The present application relates to an IRAK4-degrading protein degradation targeting chimera compound of formula (A) and a preparation method thereof, a pharmaceutical composition comprising the compound, and use of the pharmaceutical composition in treatment of diseases, disorders or conditions associated with IRAK4 protein kinase.

The present invention is based on the discovery of a proteolysis targeting compound having tissue targeting capability and use thereof, relating to medicinal products, and to such a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, or a polymorph. The compound is a proteolysis targeting chimera (PROTAC) with specific tissue targeting ability. The compound structure comprises three parts, i.e., A-BD-CON, wherein the part A is a PROTAC, one end of the structure thereof is a target protein ‘binding ligand, and the other end is a ubiquitin ligase ligand; and the part CON is a ligand of an asialoglycoprotein receptor (ASGPR), enabling the specific tissue targeting function. The compound enriches in liver tissue and is able to target cells in the tissue. The invention achieves improved druggability of the PROTAC with higher solubility and cellular membrane permeability, therefore produces enhanced pharmaceutical effect on the specific target tissue.

The present application relates to a kind of targeted degradation androgen receptor bifunctional chimeric heterocyclic compound and its purposes, specifically provides the compound shown in formula (I), or its isotopic compound, or its optical isomer, or its tautomer, or its pharmaceutically acceptable salt, or its prodrug, or its solvate, wherein, ARB is androgen receptor recognition / binding portion, L is linking portion, U is ubiquitin protease recognition / binding portion;Three parts are connected by chemical bond.The above-mentioned compound provided by the present application can target degradation androgen receptor in prostate cancer cell, and inhibit the proliferation of prostate cancer cell, also show good metabolic stability and pharmacokinetic property.The compound of the present application has good application prospect in the preparation of androgen receptor protein degradation targeting chimera, and the preparation of the drug for treating related diseases (including prostate cancer, breast cancer, Kennedy disease) regulated by androgen receptor.

The invention provides a PD-L1 protein degradation targeting chimera as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The protein degradation targeting chimera of PD-L1 provided by the invention is a PROTAC molecule based on an isoindoline structure, and the molecular weight of a warhead part of the PROTAC molecule is only 382.5070. The PD-L1 protein degradation targeting chimera provided by the invention has high PD-L1 protein degradation activity, and has excellent tumor treatment potential. In addition, the preparation method of the PD-L1 protein degradation targeting chimera is short in synthetic route, low in cost and easy to realize industrial production.

The invention provides a novel human cerebellar protein (CRBN) E3 ubiquitin ligase inhibitor which can be used for preparing PROTAC molecules. CRBNE3 ubiquitin ligase inhibitors and PROTAC molecules are useful for the treatment of cancer and other diseases.

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 invention discloses a protein degradation targeting chimera targeting FGFR4 as well as a preparation method and application thereof, and relates to the technical field of biological medicines. Wherein the protein degradation targeting chimera has a structure as shown in a formula (V1), and is formed by coupling a covalent inhibitor ligand targeting FGFR4 and an E3 ubiquitin ligase ligand through a linker; according to the preparation method, an intermediate is constructed through multi-step organic synthesis, and finally a target compound is obtained through an amide condensation reaction. The compound can be specifically combined with FGFR4 protein and induce ubiquitination degradation of the FGFR4 protein, and has a remarkable curative effect in preparation of drugs for treating FGFR4-mediated tumors. In the development of the FGFR4 targeted protein hydrolysis chimera, a lead compound with potential is provided for the first time, and the problem that the FGFR4 targeted protein hydrolysis chimera becomes available from nothing is solved.

The present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, a pharmaceutical composition containing the compound and a use thereof in treating and / or preventing BTK-related diseases.

The invention provides a ricin antidote and application thereof, and relates to the technical field of biomedicine. The ricin antidote provided by the invention comprises a first ligand, a connecting arm and a second ligand, the first ligand and the second ligand are connected through a connecting arm; the first ligand is a nucleic acid aptamer of ricin, and the nucleic acid sequence is as shown in SEQ ID NO. 1; and the second ligand is selected from an E3 ligase ligand, a hydrophobic molecule or an LC3 ligand. The ricin antidote is designed on the basis of a proteolysis targeting chimera technology, a hydrophobic labeling targeting proteolysis technology and an autophagosome binding compound technology, and a nucleic acid aptamer of ricin can be specifically bound with ricin, so that the combination of ricin and ribosome is inhibited, and irreversible damage is reduced; the degradation of the ricin is induced through an E3 ligase ligand, a hydrophobic molecule or an LC3 ligand, so that a reference is provided for related researches on the degradation of the ricin in the future.

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 following structural formula:or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.

The application discloses an FTO protein degradation targeting chimera as well as a preparation method and application thereof, and belongs to the technical field of biotechnology and biological medicine. The FTO protein degradation targeting chimera has a protein targeting chimera (PROTAC) molecular structure, and a general structural formula thereof is shown as formula I or formula II. E is an E3 ligase ligand with ubiquitination function. L is a connecting group, and the connecting group is one of an alkylene group or an alkoxy group. The FTO protein degradation targeting chimera provided by the application can effectively degrade FTO protein as an FTO protein degradation agent, thereby improving obesity and fatty liver, can be developed as a new medicine for preventing and / or treating obesity, fatty liver and diabetes, and has a wide application prospect.