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.

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 relates to a protein degradation targeting chimeric compound, a preparation method and medical application thereof, specifically to a compound as shown in a general formula (I), a preparation method of the compound, and application of the compound as a PPMTase protein degradation agent, particularly to application of the compound in prevention and / or treatment of human cancers, wherein the definition of each group in the general formula (I) is the same as the definition in the specification.

The invention relates to a bifunctional organic compound as well as a preparation method and application thereof. The bifunctional organic compound has a structure as shown in a formula (I), wherein Ris selected from at least one of alkenyl, alkynyl, substituted or unsubstituted alkyl or alkoxy; the golden larch bark acetic acid part can be specifically combined with CD147 protein, and the structure of the hydrochloride part of the protein degradation agent 1 can be combined with E3 ubiquitin ligase. The bifunctional organic compound is a small molecular protein degradation targeting chimericbody. When used for degrading the target CD147 protein, the compound can form a target protein-proteolysis targeting chimerate-E3 ubiquitinase ternary complex, then activated ubiquitin is transferredto the target protein, and finally the ubiquitinated target CD147 protein is recognized and degraded by proteasome, so that tumor cell growth is effectively inhibited.

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 an aromatic amine protein degradation chimeric compound targeting AR and BET and an application thereof, and particularly provides a compound as shown in a formula I in the description. Experimental results show that the compound can degrade AR and BRD4 in a targeted manner and reduce protein expression of the AR and the BRD4 at the same time. The compound can inhibit proliferation of various prostate cancer cells, can inhibit proliferation of a prostate cancer cell line LNCaP / AR with multiple expression of an androgen receptor AR, and also shows a good inhibition effect on prostate cancer cell lines 22RV1 resistant to prostate cancer drugs (enzalutamide) on the market. The compound also shows good metabolic stability, and has good application prospects in preparation of androgen receptor and / or BET protein degradation targeting chimeras and drugs for treating androgen receptor and BET regulated related diseases.

The invention relates to an aromatic amine compound and application thereof in the preparation of AR and BRD4 dual inhibitors and regulators. Specifically, the invention provides a compound shown as aformula I, and the compound has dual inhibition effects on AR and BRD4. The compound not only can inhibit proliferation of prostate cancer cell lines LNCaP / AR with multiple expression of androgen receptor AR, but also shows a good inhibition effect on prostate cancer cell lines VCaP and 22RV1, which are resistant to prostate cancer drugs (enzalutamide) on the market. The compound is used as a compound capable of simultaneously identifying AR and BRD4 double targets; can be used as an AR / BRD4 dual inhibitor, can also be used for preparing protein degradation targeting chimeras (PROTACs) for inducing AR / BRD4 dual-target degradation, and has a good application prospect in preparation of drugs for treating AR and BRD4 related diseases.

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 present invention relates to the technical field of medicine, in particular to a PDEδ protein degradation targeting chimera and its preparation method and application. The PDEδ protein degradation targeting chimera is a derivative with a general chemical structure (I) and its pharmaceutical Acceptable salts. Pharmacological experiments show that the derivative or salt of the present invention has strong inhibitory activity on KRAS-PDEδ protein interaction, and has strong anti-tumor activity in vitro. The present invention also provides a preparation method of the above-mentioned derivatives and pharmaceutically acceptable salts thereof. In vivo experiments show that compound (I) can effectively down-regulate the expression of PDEδ in vivo, and can significantly delay tumor growth, and can be applied to tumor diseases caused by Kras mutations. As the first reported PDEδ protein degradation targeting chimera, this kind of compound has further development and research value.

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.

The invention relates to a protein degradation targeting chimera compound, a preparation method and a medical application thereof. Specifically, the present invention relates to a compound represented by general formula (I) and its preparation method, as well as its use as a PPMTase protein degradation agent, especially in the prevention and / or treatment of human cancer. Wherein, the definition of each group in the general formula (I) is the same as that in the description.

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 an aromatic heterocyclic amine derivative as well as a preparation method and application thereof. The structural formula of the aromatic heterocyclic amine derivative is shown as a formula (I), wherein R1 is selected from chlorine, methoxyl, nitryl, hydroxyl or amino; and R2 is selected from 3, 5-dimethyl isoxazolyl or bromine. An aromatic heterocyclic amine derivative compound provided by the invention is high in water solubility and high in druggability. Similarly, the compound also has an amide structure, and the compound found by the invention has good anti-hepatitis B virus activity; the structure of the compound provided by the invention has hydroxyl and amino, so that a novel inhibitor based on a proteolysis targeting chimera mechanism can be designed and synthesized, and the derivative has a relatively great application prospect.

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.

The present invention relates to a bifunctional organic compound and its preparation method and application. The bifunctional organic compound has a structure such as formula (I): R is selected from alkenyl, alkynyl, substituted or unsubstituted alkyl or alkoxy at least one. Among them, the vitex acetic acid part can specifically bind to the CD147 protein, and the hydrochloride part of the protein degradation agent 1 can bind to the E3 ubiquitin ligase. The bifunctional organic compound is a small-molecule protein degradation targeting chimera. When used to degrade the target CD147 protein, it can form a ternary complex of target protein-protein degradation targeting chimera-E3 ubiquitinase, and then activate The ubiquitin is transferred to the target protein, and finally the ubiquitinated target CD147 protein is recognized and degraded by the proteasome, thereby effectively inhibiting the growth of tumor cells.

The invention provides a protein degradation targeting chimera with a structure as shown in a general formula (I) defined in the description and application thereof. The protein degradation targeting chimera provided by the invention can effectively inhibit the kinase activity of Bcr-Abl and a Bcr-AblT315I mutant, can inhibit the expression of Bcr-AblT315I in tumor cells, has the function of degrading Bcr-AblT315I, has a better anti-proliferation effect on tumor cells carrying Bcr-Abl or Bcr-AblT315I, and can be used as a potential drug for anti-tumor treatment.

The invention discloses a proteolysis targeting chimera. The proteolysis targeting chimera can effectively induce FLT3-ITD degradation in FLT3-ITD positive cells MOM-13 and MV-4-11 in a dose-dependent mode and a time-dependent mode. In-vivo researches show that the proteolysis targeting chimera can significantly reduce the CD45+ positive cell level in mice with acute myelogenous leukemia, and shows a good treatment effect on acute myelogenous leukemia.