40 results about "Proteolysis targeting chimera" patented technology

The present invention includes novel compounds and methods for preventing or treating diseases associated with and/or caused by overexpression and/or uncontrolled activation of a tyrosine kinase in a subject in need thereof. In certain embodiments, the compounds of the present invention comprise a tyrosine kinase inhibitor, a linker and a ubiquitin ligase binder. The methods of the present invention comprise administering to the subject an pharmaceutically effective amount of at least one compound of the invention.

There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, and to their utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for their preparation thereof, and use in medicine. There is particularly provided novel small molecule E3 ubiquitin ligase protein binding inhibitor compounds based on a fluorohydroxyproline scaffold, to their utility as ligands in synthesizing novel PROTACs, and to synthetic methods therefor.

The invention relates to a proteolytic targeting chimera, and a preparation method and application thereof. The structure of the proteolytic targeting chimera is as in the description, wherein L is aconnecting group containing at least one heteroatom of N and O, and can be used to connect a pseudolaric acid part capable of being specifically combined with a target CD147 protein and a thalidomidepart capable of being connected with E3 ubiquitin ligase. Through simultaneous action on the target protein and the E3 ubiquitin ligase, activated ubiquitin is transferred to the target protein, so that selective ubiquitination on the target protein is realized, and finally the ubiquitinated target protein is recognized and degraded by a proteasome. The preparation method of the compound is simpleand is easy to realize, and the proteolytic targeting chimera can obviously reduce the level of the CD147 protein, and has high application value in preparation of medicaments for treating or preventing cancers, in particular in preparation of antitumor medicaments taking CD147 as a target point.

The invention relates to an E3 ligase DCAF15 small molecule ligand compound and a bifunctional compound containing the same. According to the description of the invention, the bifunctional compound isused as a degradation agent of target proteins based on a protein degradation targeting chimeric body (PROTAC) technology. The invention describes the bifunctional compound, one end of the bifunctional compound contains a ligand combined with E3 ligase DCAF15, the other end of the bifunctional compound contains a ligand combined with a target protein, and the target protein is placed near the E3ligase DCAF15 through proper connecting group connection to realize ubiquitination degradation of the target protein. The synthetizable compound has good pharmacological activity of degrading target protein in vitro and vivo, so that the synthetizable compound has a wide application prospect in the aspect of degrading various pathogenic proteins.

The invention provides a GPX4 protein degradation agent, a preparation method thereof, and an anti-tumor cell drug, and belongs to the technical field of drug application. The GPX4 protein degradation agent provided by the invention has a protein degradation targeting chimera (PROTAC) molecular structure, a mother nucleus structure of the GPX4 protein degradation agent is used as a small molecule ligand for combining target protein, an A2 substituent is used as a small molecule ligand for combining an E3 ubiquitin ligase compound, and an A1 substituent is used as a connecting group for connecting the two ligands. The GPX4 protein degradation agent with the structure can specifically recognize GPX4 protein and effectively ubiquitinate and degrade the GPX4 protein, so that tumor cell ferroptosis is induced.

The invention provides a novel protein degradation targeting chimeric compound, application and a preparation method thereof. The protein degradation targeting chimeric compound is 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. The preparation method comprises the following steps: S1, carrying out a fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride; and step S2, carrying out a condensation reaction on the 3-fluorophthalic anhydride and 3-amino-2, 6-piperidinedione hydrochloride so as to obtain the 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. According to the protein degradation targeting chimeric body, the compound is moderate in molecular size, good in fluorine leaving performance, small in molecular weight and stable in performance, target protein and E3 ubiquitin enzyme can be effectively close to each other, and the protein degradation targeting chimeric body can be effectively used for preparing targeting drugs. And the preparation method is simple and convenient, less in three wastes and low in raw material price, so that the preparation cost is low, and the method is suitable for industrial large-scaleproduction.

The invention relates to a hydroxyproline derivative for preparing proteolysis targeting chimeras (PROTACs). Particularly, the invention relates to a novel micromolecule E3 ubiquitin ligase protein binding ligand compound and a compound of PROTACs, a preparation method thereof, and application of the novel micromolecule E3 ubiquitin ligase protein binding ligand compound and the compound of PROTACs in medicine. The invention relates to an E3 ubiquitin ligase protein binding ligand compound as shown in a general formula (IM) and a compound of PROTACs as shown in a general formula (I), a preparation method thereof, and application of the E3 ubiquitin ligase protein binding ligand compound as shown in the general formula (IM) and the compound of PROTACs as shown in the general formula (I) in medicine.

The invention provides a proteolysis targeting chimera and application thereof. According to a technical scheme in the invention, a novel PROTAC degradation agent compound 21a is developed on the basis of a BMS-37 small molecule. The novel PROTAC degradation agent compound 21a is an example of degrading membrane proteins on the basis of a ligand binding to the extracellular domain of a PD-L1 protein, and can effectively degrade PD-L1 in various malignant tumor cells. In-vivo research results show that after treatment with the compound 21a, the compound 21a can significantly reduce the level of the PD-L1 in tumors, promote infiltration of CD8<+>T cells and significantly inhibit growth of mouse colorectal cancer MC-38 cells. The PROTAC molecule is expected to be one of novel and alternative strategies for cancer immunotherapy.

The present invention relates to a protein degradation targeting chimeric body, a preparation method and application thereof, the protein degradation targeting chimeric body has a structure represented by the formula shown in the specification, the protein degradation targeting chimeric body is a heterocyclic ring-containing linking group, and the heterocyclic ring contains at least one N atom. The protein degradation targeting chimeric body connects a Pseudolaric Acid B part which can be specifically combined with a target CD147 protein and a thalidomide part which can be combined with E3 ubiquitin ligase; the protein degradation targeting chimeric body is capable of simultaneously acting on a target protein and the E3 ubiquitin ligase; activated ubiquitin is transferred to the target protein, selective ubiquitination of the target protein is achieved, finally, the ubiquitinated target protein is recognized and degraded by proteasome, and the protein degradation targeting chimeric body has very high application value in preparation of drugs for treating or preventing cancer, especially in preparation of anti-tumor drugs with the CD147 as a target point.

The invention relates to the technical field of medicine, in particular to a PDE[delta] protein degradation targeting chimera, and a preparation method and application thereof. The PDE[delta] proteindegradation targeting chimera is derivatives having a general chemical formula (I) and pharmaceutically acceptable salts thereof. Pharmacological experiments show that the derivatives or salts have astrong inhibitory activity on KRAS-PDE[dela] protein interactions, and have strong in-vitro antitumor activity. The invention also provides a method for preparing the above-mentioned derivatives and the pharmaceutically acceptable salts thereof. In-vivo experiments show that compounds (I) can effectively down-regulate the expression of PDE[delta] in vivo, can significantly delay tumor growth, andcan be applied to tumor diseases caused by Kras mutation. The compounds, as the PDE[delta] protein degradation targeting chimera, have further development and research value.

The invention provides a protein degradation targeting chimera as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the protein degradation targeting chimera comprises the following structure: an MDM2 target protein inhibitor-C (O) NH-L2-Y1-B1, and the definition of each group is described in the specification. The compounds are useful in the treatment of conditions or disorders (e.g., cancer) responsive to degradation of the MDM2 protein.

The present invention relates to bi-functional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods for using same. More specifically, the present disclosure provides specific proteolysis targeting chimera (PROTAC) molecules which find utility as modulators of targeted ubiquitinization of a variety of polypeptides and other proteins, in particular the androgen receptor of a slice variant of AR which lacks the LBD, labelled as AR-V7, which are then degraded and/or otherwise inhibited by the compounds as described herein.

The invention belongs to the technical field of medicines, and particularly relates to an mTOR protein degradation targeting chimera as well as a preparation method and application thereof. The mTOR protein degradation targeting chimera compound disclosed by the invention shows a strong mTOR inhibition capability and inhibits the proliferation of MCF-7. The compound P1 can reduce the expression of mTOR downstream protein p-S6 (Ser240/244) and p-AKT (Ser473), and further research shows that the compound inhibits the growth of cancer cells by inducing autophagy, and has no influence on cell apoptosis or cell cycle.

The invention provides a polypeptide PROTAC molecule and a preparation method and application thereof, the polypeptide nano protein ubiquitination degradation agent is a proteolysis targeting chimera based on a ubiquitination-proteasome system, and the polypeptide nano protein ubiquitination degradation agent comprises a module molecule, the module molecule comprises a module molecule A and a module molecule B, the module molecule A comprises a coupling group A, a self-assembly group and an E3 ligase recognition group, the module molecule B comprises a coupling group B, a self-assembly group and a targeted binding group, and the coupling group A and the coupling group B are used for connecting the module molecule A and the module molecule B. The polypeptide nano protein ubiquitination degradation agent can realize dose-dependent degradation, can be specifically triggered in a tumor area, remarkably reduces off-target toxicity, and is a protein ubiquitination degradation agent with selectivity and specificity.

An aromatic amine androgen receptor (AR) and BET targeting protein degradation chimera compound is represented by formula I. Experimental results show that the compound can target and degrade both AR and BRD4, and down-regulate the expression of AR and BRD4 proteins; the compound can inhibit the proliferation of a variety of prostate cancer cells; the compound can inhibit the proliferation of a prostate cancer cell line LNCaP/AR, which overexpresses the AR, and can achieve a good inhibition effect on a prostate cancer cell line 22RV1, which is resistant to a marketed prostate cancer drug (enzalutamide). The compound also shows good metabolic stability, and has a good application prospect in the preparation of an AR and/or BET protein degradation targeting chimera, and a drug for the treatment of related diseases regulated by the AR and BET.

The invention discloses a protein degradation targeted chimera linker generation method based on deep reinforcement learning, which comprises the following steps: expanding a constructed ZINC data set and a PROTAC data set by using a data enhancement method, and taking the obtained first ZINC data set and first PROTAC data set as a supervision training set; constructing a Transform model, and setting a training step number, a network layer number, an attention layer number and optimizer parameters; training a Transform model by using the first ZINC data set, and training and updating the Transform model by using an objective function and a back propagation algorithm; the first PROTAC data set is used for training the updated Transform model, the Transform model is migrated to a PROTAC target domain, and a Prior prior model is obtained; inputting the segment pair SMILES into a Prior prior model for batch generation, scoring the generated PROTAC by using a scoring function, introducing a strategy gradient algorithm of reinforcement learning, and updating an Agent model; repeating until the PROTAC score is no longer increased or the training step number is reached; and the updated Agent model is utilized to realize large-scale generation of the protein degradation targeted chimera linker conforming to expected attributes under the condition of given fragment pairs.