CN117982498A - Composition containing protein degradation agent or inhibitor and application thereof - Google Patents

Composition containing protein degradation agent or inhibitor and application thereof Download PDF

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CN117982498A
CN117982498A CN202311438245.8A CN202311438245A CN117982498A CN 117982498 A CN117982498 A CN 117982498A CN 202311438245 A CN202311438245 A CN 202311438245A CN 117982498 A CN117982498 A CN 117982498A
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optionally substituted
cancer
inhibitor
chr
halogen
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童友之
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Suzhou Kintor Pharmaceuticals Inc
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Suzhou Kintor Pharmaceuticals Inc
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Abstract

The present invention relates to a pharmaceutical composition for the treatment of cancer comprising a protein degrading agent or inhibitor, a CDK4/6 inhibitor. The pharmaceutical composition provided by the invention has excellent tumor inhibition effect, has obvious synergistic effect and is superior to the effect of independently using medicines.

Description

Composition containing protein degradation agent or inhibitor and application thereof
Technical Field
The invention belongs to the field of medicines, and relates to a composition containing a protein degradation agent or inhibitor and application thereof.
Background
The tumor molecular targeting treatment is to use the marker molecules of tumor cells as targets and intervene in the link of cancerous change of the cells. The tumor growth factor receptor, signaling molecule, cyclin, apoptosis regulator, proteolytic enzyme, vascular endothelial growth factor, etc. may be used as the molecular target for tumor treatment.
The natural disordered protein C-MYC is an important transcription factor and plays a vital role in cell proliferation, differentiation and apoptosis. Expression of MYC genes is tightly regulated in normal cells, and abnormal expression can lead to the occurrence of cancer. C-MYC can promote the development and growth of tumors in several ways (C Yu, et al scientific reports 6.1 (2016): 1-11). Numerous studies have shown that C-MYC is closely associated with a variety of neoplastic diseases including lymphoma, breast cancer, prostate cancer, colon cancer, cervical cancer, multiple myeloma, myelogenous leukemia, melanoma, osteosarcoma, glioblastoma, small cell lung cancer, and medulloblastoma. The action types of the existing C-MYC inhibitors mainly comprise: inhibiting binding of MYC to Max proteins, such as the polypeptide drug OMO-103 developed by Peptomyc company, is in clinical trials (NCT 04808362); inhibiting expression of MYC, from a gene or mRNA perspective, inhibiting expression levels of MYC proteins, thereby inhibiting MYC function, e.g., mycro, kj Pyr 9; and (5) targeted degradation of MYC proteins and the like. Because C-MYC is a naturally disordered protein, the lack of available drug recognition sites, the design and development of C-MYC target drugs is a great challenge, and no targeted therapies have been approved at present. Applicants have filed a number of C-MYC inhibitors or degradants, such as PCT/CN2020/100103, PCT/CN2021/127229, PCT/CN2022/100078, CN202210916308.5, CN202111599314.4 and PCT/CN2022/141113.
The cell cycle is regulated by a group of Cyclin Dependent Kinases (CDKs), CDK4/6, i.e. cyclin dependent kinases 4 and 6, are overexpressed in many malignancies, exhibiting significant activity, contributing to proliferation and spread of cancer cells. Many CDK4/6 inhibitors have been approved for sale or in clinical trials, such as Palbociclib (Palbociclib) at pyroxene, ribociclib (rebabociclib) at North, abemaciclib (Abeli) at Gift, SHR6390 (darzeli) at Henry, trilaciclib (trorascily) at the pioneer pharmaceutical industry, and the like. CDK4/6 inhibitors such as Palbociclib show significant clinical efficacy in breast cancer, but as with other kinases, their efficacy may be limited over time by the development of primary or acquired resistance.
Disclosure of Invention
In order to solve the problem of poor drug resistance and single use efficacy of CDK4/6 inhibitors, the present invention provides a pharmaceutical composition comprising a protein degradation agent or inhibitor and a CDK4/6 inhibitor; the protein degradation agent or inhibitor can degrade or inhibit any one or more proteins of C-MYC, N-MYC, GSPT1, CK1 alpha and IKZF (1/2/3).
In one embodiment of the application, the protein degrading agent or inhibitor of the application is a degradable or inhibits C-MYC protein. The protein degrading agent or inhibitor of the present application may be selected from compounds of any structure of PCT/CN2020/100103, PCT/CN2021/127229, PCT/CN2022/100078, CN202210916308.5, CN202111599314.4 and PCT/CN2022/141113, which are incorporated herein by reference in their entirety.
In one embodiment of the invention, the protein degrading agent or inhibitor is a compound having the structure of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof.
Wherein,
W is selected from: c (R W)2, c= O, C = S, NH or-N-C 1-6 alkyl;
R W is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
G is selected from: H. a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted with a group selected from the group consisting of: hydroxy, -OPO (OR G)2、-OCORG, carboxy, -OS (O) 1-2RG, sulfonate, each R G is independently selected from H, C 1-4 alkyl;
t 1-T3 is independently selected from: o or S;
A 1-A3 is independently selected from: c (R A)2, each R A is independently selected from H, halogen, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R', -COOR ', -OR', -NR 'R';
q 1-Q4 is independently selected from: CR Q or N;
R Q is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
R 'and R' are independently selected from: H. c 1-15 alkyl optionally substituted with halogen, C 3-6 cycloalkyl;
l 1 represents a linking group;
ring Z represents an optionally substituted heterocycloalkyl group containing at least one N atom as a heteroatom, which is linked to L 2 by N;
l 2 is selected from: a bond, a group represented by the following general structure:
-(CHR1)k-；
-(CHR1)m-O-(CHR1)n-；
-(CHR1)m-N(R1)-(CHR1)n-；
-(CHR1)m-CO-(CHR1)n-；
-(CHR1)m-CO-N(R1)-(CHR1)n-；
-(CHR1)m-N(R1)-CO-(CHR1)n-；
Wherein k is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, m and n are independently selected from: 0.1, 2, 3, 4, 5, 6, each R 1 is independently selected from: H. c 1-6 alkyl optionally substituted with halogen;
cy 1 is selected from: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl or optionally substituted biaryl;
Cy 2 is selected from H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl, or optionally substituted biaryl;
u is selected from 0, 1,2, 3, 4, 5.
In one embodiment of the present invention, the compound having the structure of formula (I) is selected from the following A1-A117:
Preferably, the protein degrading agent or inhibitor is selected from the group consisting of a compound of formula a80 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof.
In one embodiment of the invention, the a80 pharmaceutically acceptable salt is selected from the hydrochloride salt.
In one embodiment of the invention said CDK4/6 inhibitor is selected from the group consisting of Palbociclib (Pabociclib), ribociclib (Rabociclib), abemaciclib (Abeli), SHR6390 (Darcril), trilaciclib (Triac )、Flavorpiridol(Alvocidib)、Flavorpiridol HCl、AT7519、AT7519HCl、Milciclib(PHA-848125)、R547、Riviciclib hydrochloride(P276-00)、FN-1501、Dalpiciclib、PF-06873600、CDKI-73、MC180295、G1T38、ON123300、FLX-925、BPI-1178、AG-024322、NSC625987、CGP-82996、AMG925, is preferably Palbociclib, ribociclib, abemaciclib, SHR6390, trilaciclib, more preferably Palbociclib).
In one embodiment of the invention, the protein degrading agent or inhibitor is the hydrochloride salt of A80 or a hydrate or solvate thereof and the CDK4/6 inhibitor is Palbociclib.
In one embodiment of the present invention, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, diluents or carriers.
In one embodiment of the invention, the pharmaceutical composition may further comprise at least one other anticancer agent, such as a platinum agent, (e.g. cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973); anti-microtubule agents, (e.g., vinca alkaloids such as vincristine, vinblastine, taxanes such as paclitaxel, docetaxel); antimetabolites (e.g., 5-fluorouracil, methotrexate, fludarabine); alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as dichloroethyl nitrosourea and hydroxyurea); anthracyclines (e.g., doxorubicin, daunorubicin); antitumor antibiotics (e.g., mitomycin, idarubicin, doxorubicin, daunomycin); topoisomerase inhibitors (e.g. etoposide, camptothecins); anti-angiogenic agents (e.g., bevacizumab); or any other cytotoxic agent (e.g., estramustine phosphate, prednisone mustard, hormone) or hormone agonist, antagonist, partial agonist or partial antagonist, kinase inhibitor.
In one embodiment of the present invention, the present invention provides the use of the above composition for the preparation of a medicament for the treatment of cancer.
In one embodiment of the present invention, the present invention provides the above composition for use in the treatment of cancer.
In one embodiment of the invention, the invention provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the above composition.
In one embodiment of the present invention, the present invention provides a composition as described above for use as a medicament.
In one embodiment of the invention, the cancer is selected from the group consisting of leukemia, lymphoma, medulloblastoma, melanoma, multiple myeloma, glioblastoma, osteosarcoma, liver cancer, lung cancer, kidney cancer, pancreatic cancer, oral cancer, stomach cancer, esophageal cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, breast cancer, human ductal carcinoma, colon cancer, rectal cancer, cervical cancer, ovarian cancer, prostate cancer, bladder cancer, human transitional cell carcinoma of the bladder, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, small cell lung cancer.
In one embodiment of the invention, the cancer is selected from transitional cell bladder cancer or bladder cancer.
In one embodiment of the present invention, the protein degrading agent or inhibitor in the above composition is a compound having the structure of formula (I); preferably, the cancer is selected from transitional cell bladder cancer or bladder cancer; further preferably, the CDK4/6 inhibitor is Palbociclib.
In one embodiment of the present invention, the protein degrading agent or inhibitor in the above composition is selected from the group consisting of a compound of the structure A1-a117 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof; preferably, the cancer is selected from transitional cell bladder cancer or bladder cancer; further preferably, the CDK4/6 inhibitor is Palbociclib.
In one embodiment of the present invention, the protein degrading agent or inhibitor in the above composition is selected from a compound of the a80 structure or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof; preferably, the cancer is selected from transitional cell bladder cancer or bladder cancer; further preferably, the CDK4/6 inhibitor is Palbociclib.
In one embodiment of the invention, the protein degrading agent or inhibitor and CDK4/6 inhibitor in the composition are administered in combination, or the protein degrading agent or inhibitor and CDK4/6 inhibitor are administered after being prepared into a compound preparation.
In one embodiment of the invention, the weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug to CDK4/6 inhibitor is from 0.01:1 to 100:1, preferably 0.01:1、0.05:1、0.1:1、0.2:1、0.5:1、1:1、1.5:1、2:1、3:1、5:1、8:1、10:1、15:1、20:1、25:1、30:1、40:1、50:1、60:1、70:1、80:1、90:1、100:1.
In one embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug and CDK4/6 inhibitor thereof may be a single composition or a separate composition.
In one embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof is administered in a dose of 1 to 500mg, preferably 50 to 200mg, more preferably 100 to 150mg; the administration frequency is once a day, twice a day, three times a day, preferably once a day.
In one embodiment of the invention, the CDK4/6 inhibitor is administered in an amount of 1 to 500mg, preferably 50 to 200mg, more preferably 100 to 150mg; the administration frequency is once a day, twice a day, three times a day, preferably once a day.
The route of administration in the present invention is not limited to oral administration, parenteral administration, transdermal administration, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection. In certain embodiments, both drugs may be designed for oral or injectable administration, or one drug may be designed for oral administration and the other drug may be designed for injectable administration.
The present invention provides a method for preventing/treating cancer comprising administering to a subject a therapeutically effective amount of a C-MYC protein degrading agent having the structure of formula (I) as described above and a CDK4/6 inhibitor.
The invention has the beneficial effects that:
The pharmaceutical composition provided by the invention combines a protein degradation agent, in particular a compound with a structure shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug and CDK4/6 inhibitor thereof, and has obvious synergistic effect; can obviously inhibit cell proliferation and tumor growth, and is obviously better than the effect of independently using the medicines.
Drawings
FIG. 1 is a graph showing degradation of MYC and GSPT1 proteins in HL60 cells by a compound
FIG. 2 is a graph of degradation of MYC proteins in A80.HCl versus 5637 cells and T24 cells.
FIG. 3 is a graph of degradation of MYC proteins in DU145 cells and C4-2B cells by A80. HCl.
FIG. 4 is a graph of degradation of MYC proteins in MDA-MB-231 cells and T47D cells by A80. HCl.
FIG. 5 shows the proliferation activity of A80.HCl in inhibiting T24 cells and 5637 cells.
FIG. 6 shows the activity of HCl in inhibiting DU145, C4-2B, MDA-MB-231, T47D cell proliferation.
FIG. 7 shows the inhibition of T24 and 5637 cell proliferation activity by Palbociclib alone in combination with A80. HCl.
FIG. 8 is a graph of A80.HCl inhibition of T24 and 5637 cell clonogenic (left) and their corresponding statistical analysis (right).
FIG. 9 shows the inhibition of DU145, C4-2B, MDA-MB-231, T47D cell clone formation by A80. HCl.
FIG. 10 is a corresponding statistical analysis of the formation of HCl inhibited DU145, C4-2B, MDA-MB-231, T47D cell clones.
FIG. 11 shows the inhibition of T24 and 5637 cell clone formation and corresponding statistical analysis for Palbociclib and A80.HCl single and combined applications.
FIG. 12 is a graph of Palbociclib, A80.HCl alone and in combination, inhibition of T24 nude mice xenograft tumor growth (left panel of day 30 tumor actual size, right panel of tumor size versus time).
FIG. 13 is a graph of Palbociclib, A80.HCl alone and in combination with inhibition of 5637 nude mice xenograft tumor growth (left panel of day 30 tumor actual size, right panel of tumor size versus time).
CDK4/6i in FIGS. 11-13 refers to CDK4/6 inhibitors, specifically Palbociclib.
The specific embodiment is as follows:
Definition of the definition
Unless defined otherwise, terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The term "pharmaceutical composition" means a product comprising an active ingredient, at least one pharmaceutically acceptable excipient. The pharmaceutical compositions of the present invention encompass any composition made from admixing the active ingredient, additional active ingredient, and pharmaceutically acceptable excipients.
The term "tumor" is malignant and is used interchangeably with "cancer". Tumor growth inhibition or regression may be localized to a single tumor or group of tumors within a particular tissue or organ, or may be systemic (i.e., affecting tumors in all tissues or organs).
The term "effective amount" means an amount of a pharmaceutically active ingredient sufficient to affect a disease or condition after administration to an individual/subject/patient in order to prevent, alleviate and/or treat the disease or condition. The "effective amount" may vary depending on factors such as the pharmaceutically active ingredient, the symptoms or severity of the disease or condition, the individual/subject/patient's personal condition (such as age, sex, weight, etc.), and the like.
The term "pharmaceutically acceptable carrier and/or excipient" refers to a carrier and/or excipient that is pharmacologically and/or physiologically compatible with the subject and active ingredient, as is well known in the art (see, e.g., Remington'sPharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995), and including, but not limited to, pH modifiers, surfactants, adjuvants, ionic strength enhancers).
Unless otherwise indicated, the term "compound" refers to any particular compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof. The term compound, as used in this context, generally refers not only to a single compound, but may include other compounds, such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures), as well as specific enantiomers or mixtures of enantiomers of the disclosed compounds. The term also refers in this context to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to an active site.
The term "pharmaceutically acceptable salt" is used to describe a salt form of one or more compounds described herein, which is provided to increase the solubility of the compound in the gastric juice of the gastrointestinal tract of a patient in order to promote dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals (e.g., potassium and sodium), alkaline earth metals (e.g., calcium, magnesium, and ammonium salts), and many other acids and bases well known in the pharmaceutical arts.
The term "prodrug" refers to a functional derivative of the compound that is readily converted to the desired compound in vivo. Thus, the method is applicable to a variety of applications. In the methods of treatment of the present invention, the term "administering" will include treatment of the various conditions described with a specifically disclosed compound or with a compound that may not be specifically disclosed but that is convertible in vivo to a specific compound upon administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", H.Bundgaard, elsevier et al, 1985.
The compounds of the present invention may form solvates with conventional organic solvents, or hydrates with water, and such solvates or hydrates are also intended to be included within the scope of the present invention.
In the compounds of the present invention, all tautomers and mixtures thereof in any ratio are included.
The term "combination" as used herein refers to a mode of administration wherein at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug and CDK4/6 inhibitor thereof is administered over a period of time, wherein both agents exhibit pharmacological effects. The order of administration may be that the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof is administered simultaneously with the CDK4/6 inhibitor; or administering the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof, after a specified time interval, prior to administration of the CDK4/6 inhibitor; or administering the CDK4/6 inhibitor first, after a specified time interval, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, prodrug thereof; the specific time interval is 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days. When administered in combination, the therapeutically effective amount of each compound may be less than the therapeutically effective amount of each compound administered alone.
A80.HCl in the present invention means that one molecule of A80 hydrochloride contains 2 molecules of hydrochloric acid.
The application is further described below in connection with examples, which are not intended to limit the scope of the application. Experimental materials and detection methods:
1. Reagents and sources
2. Cell lines and sources
The cell lines used in the present invention were all purchased from AMEICAN TYPE Culture Collection.
Cell lines Goods number
Human bladder transitional cell carcinoma cell T24 HTB-4
Human bladder cancer cells 5637 HTB-9
Human prostate cancer cells C4-2B CRL-3314
Human prostate cancer cells DU145 HTB-81
Human breast cancer cell MDA-MB-231 HTB-26
Human breast ductal carcinoma cells T47D HTB-133
Example one, test of the antiproliferative potential of Compounds A1-A117 on HL60 cells
1. Cell plating
HL60 (national academy of sciences cell bank) cells in the logarithmic growth phase were counted and spread evenly in 96-well transparent bottom white plates with a cell number of 20000 cells per well of 100 μl per well.
2. Cell drug addition
An amount of the compound of the present invention was weighed and diluted with DMSO to a concentration of 10 mM. The cell-corresponding culture medium RPMI-1640 (meilunbio, MA 0215) was taken, the compound was diluted to the concentration required for the experiment, and mixed with gentle shaking. mu.L of diluted compound gradient dilutions were added to the plated cells per well, and 50. Mu.L of 0.1% DMSO was added to the control group, and mixed gently with shaking. Placing the cells in a cell culture box, and incubating for 3 days.
CTG detection
3.1 CellTiter-Glo TM (CTG) (purchased from Promega under the trade designation G9242) reagent was equilibrated to room temperature in advance, protected from light, from a refrigerator at-20 ℃. CELL TITER-Glo buffer and CELL TITER-Glo substrate are mixed according to a ratio of 1:1 to prepare the CTG detection reagent.
3.2 And taking out the 96-well plate, and checking by a microscope to see the growth condition.
3.3, The bottom of the 96-well plate taken out is stuck by white paper, then is covered by tin foil paper, and is vibrated and shaken uniformly at 37 ℃ for 300r and 10 min.
3.4 Add 50. Mu.L CTG detection reagent per well, and perform detection of Lumineancence signal by a Biotek Synergy H1, and calculate inhibition rate. Compound IC 50 values were calculated by XLfit 5.5.0 software and HL60 cell proliferation inhibitory activity was assessed and experimental results are shown in table 1.
TABLE 1 anti-HL 60 cell proliferation Activity of Compounds A1-A117
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Example two, compounds A1-A117 test for the ability of Compounds A1-A117 to degrade C-MYC and GSPT protein in HL60 cells
1. Cytopharmaceutical treatment and protein extraction
1.1 Cell treatment
HL60 cells in exponential growth phase, cells were plated into 6-well plates after digestion of the cells, 1×10 6 cells per well, RPMI-1640 (meilunbio, MA 0215) as cell culture medium, and after one day of cell wall-attached growth, compound A1-a117 was added as test drug for culture, and protein was extracted after 24 hours (Ctrl is just added with equal volume of DMSO).
1.2 Cell protein extraction
Cell removal medium RPMI-1640 (meilunbio, MA 0215) in a 6-well plate is carried out, cells are digested by PBS once, and are respectively centrifugally collected in a 1.5mL centrifuge tube, 100 mu LRIPA lysate (containing 100 mu M PMSF) is added into each tube, after full mixing, the mixture is kept on ice for 30min, and then the mixture is centrifuged at 12000rpm for 20min at 4 ℃ of a centrifuge, the supernatant is taken for Western bloting experiments, and samples can be stored at-80 ℃.
1.3 Protein concentration determination
Using BCA protein concentration assay kit (from Thermo Fisher, cat No. 23225), BSA standard assay solution and test sample (test sample can be diluted and tested) were prepared according to table a below, using 96-well plates, adding 200 μl BCA working solution (prepared according to kit) after each well was made up to 20 μl with PBS, mixing well, standing at 60 ℃ for 10min, detecting absorbance at 562nm, recording the readings, using standard concentration gradient as standard curve, substituting sample absorbance to calculate sample protein concentration (table a).
Table A protein quantitative standard preparation
2.Western bloting Standard procedure of experiment
2.1 Protein denaturation
RIPA protein lysate (purchased from Solarbio, cat. No. R0010) was added to 5X Loading Buffer (SDS, glycerol, bromophenol blue, TRIS) (purchased from Solarbio, cat. No. P1040) and denatured at 100℃for 5min.
2.2 Sample application and electrophoresis
After applying a 10% pre-gel and a special electrophoresis solution, each well was subjected to electrophoresis at 200V for 30min after applying a homogeneous protein sample and protein ladder (purchased from thermo, cat. Number 26617).
2.3 Closure
The excess is cut off after the glue is removed, and the glue is transferred to a PVDF film by a wet transfer method (the PVDF film is required to be activated by methanol for 1min and then used), 300mA is needed, and a large amount of heat is generated in the film transfer process, and the temperature is required to be reduced by an ice box.
The PVDF membrane after the membrane transfer was put in 5% skim milk and shaken at room temperature for 1h.
2.4 Incubation of primary antibodies
PVDF membrane was cut off according to the indicated molecular weight on the marker, placed in C-MYC (purchased from abcam, cat No. ab 32072) or GSPT1 (purchased from abcam, cat No. ab 234433) or CK1 alpha (purchased from abcam, cat No. ab 206652) or IKZF2 (purchased from proteintech, cat No. 13554-1-AP) and GAPDH (purchased from CST, cat No. # 97166) respectively, the antibody was diluted with TBST buffer (TRIS, KCL and NaCl) at a ratio of 1:1000, adjusted to pH7.4 with hydrochloric acid, and Tween 20 was added) and blocked overnight at 4 ℃.
2.5 Incubation of secondary antibodies
The PVDF membrane after incubation of the primary antibodies was washed 3 times with TBST for 10min each on a shaker, after washing the membranes were placed in the corresponding secondary antibodies, respectively, and the shaker was shaken and incubated for 2h at room temperature.
2.6 Film washing and Exposure
After the incubation of the secondary antibodies, the membrane was placed in TBST and washed by shaking in a shaker for 3 times, 10min each time, and fluorescence on the membrane was excited by ECL method after washing.
2.7 Protein residual amount
The grey value of the western blot, i.e. the corresponding protein remaining amount, was measured using Image J (1.8.0) software. The experimental results are shown in tables 2-4, and FIG. 1.
TABLE 2 degradation of C-MYC protein Activity by Compounds
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Note that: the @10nM/Ctrl refers to the percentage of the residual amount of C-MYC protein at 10nM of the compound to the residual amount of C-MYC protein of the Ctrl group to evaluate the activity of the compound to degrade the C-MYC protein.
TABLE 3 degradation GSPT protein Activity of Compounds
Note that: the @10nM/Ctrl refers to the percentage of GSPT protein remaining at 10nM of compound to GSPT protein remaining in the Ctrl group to assess compound degradation GSPT1 protein activity.
TABLE 4 degradation of CK1 alpha and IKZF2 protein Activity by Compounds
Note that: the CAS number for CC-90009 is 1860875-51-9. The @10nM/Ctrl refers to the percentage of the residual amount of CK1 alpha protein at 10nM of the compound to the residual amount of CK1 alpha protein in the Ctrl group to evaluate the activity of the compound to degrade the CK1 alpha protein, IKZF 2.
EXAMPLE three preparation of A80 hydrochloride (A80. HCl)
Synthesis of Compound A80-2
Compound A80-1 (30.00 g,115.87 mmol) was dissolved in 100mL of DMF, to which was added compound 4-hydroxymethylpiperidine (15.99 g,139.05 mmol) and K 2CO3 (31.98 g,231.75 mmol). After stirring the reaction at 90 ℃ for 2h, TLC showed complete reaction. Water was added, extraction with ethyl acetate (250 ml x 3), the organic phases were combined, washed with saturated NaCl solution (150 ml x 3), dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, eluent PE (petroleum ether): EA (ethyl acetate) =3:1, giving product a80-2 (34.80 g, 89%).
Synthesis of Compound A80-3
Compound a80-2 (34.80 g,102.96 mmol) was placed in a 250ml round bottom flask and H 2 O:1,4-Dioxane = 1:4 in a mixed solvent of 150mL, then adding thereto the compound 3-chlorobenzeneboronic acid (16.06 g,102.96 mmol), K 2CO3 (28.42 g,205.92 mmol) and Pd (PPh 3)4 (5.95 g,5.15 mmol) in turn, stirring at 80 ℃ under protection of N 2, reacting overnight, LCMS monitoring reaction complete, adding water, extracting with ethyl acetate (250 mL x 3), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, separating and purifying with column chromatography, eluent PE: ea=3:1, to give the product a80-3 (32.40 g, 85%).
Synthesis of Compound A80-4
Compound A80-3 (32.40 g,87.58 mmol) was dissolved in 200mL of dichloromethane, and dess-Martin reagent (44.55 g,105.08 mmol) was slowly added under ice-bath conditions and after stirring at room temperature for 1h, TLC showed complete reaction. Saturated NaHCO 3 was added, quenched, water was added, extracted with DCM (dichloromethane) (2500 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography, eluent PE dcm=1: 1 to give product A80-4 (23.50 g, 73%).
Synthesis of Compound A80
Compound A80-4 (23.50 g,63.86 mmol) was dissolved in 350mL MeOH, then 3- (6-aminomethylene-3-oxo-1H-isoindol-2-yl) piperidine-2, 6-dione hydrochloride (19.80 g,63.86 mmol) was added, 3mL glacial acetic acid was added dropwise, after stirring at room temperature for 30min, sodium cyanoborohydride (8.05 g,127.72 mmol) was added slowly under ice bath, the reaction was stirred at room temperature for 1H, and TLC thin layer plates monitored for completion. After addition of saturated NaHCO 3 (150 mL), water was added, extracted with DCM (500 mL x 3), the organic phases were combined, concentrated and washed with EA to give crude 18.75g. Then with DCM: ACN: meoh=1: 1:1 together with 210mL of the mixed solvent, and 14.51g of the product is obtained by filtration. After further mixing 100mL of 1N HCl and 100mL of tetrahydrofuran, the pH was adjusted to neutral with saturated NaHCO 3 and filtered to give product A80 (10.98 g, 28%).
Synthesis of Compound A80.HCl
Compound A80 (10.98 g,17.57 mmol) was dissolved in 400mL of ACN, followed by 15mL of ethyl acetate solution of hydrogen chloride (2M), the reaction was stirred at room temperature for 1h, the solvent was dried, and then slurried with a mixture of methyl tert-butyl ether and ethyl acetate (120 mL:20 mL), and filtered to give the product A80.HCl (10.73 g, 87%).
1H NMR(400MHz,DMSO)δ11.00(s,1H),9.28(br s,2H),8.84(d,J＝1.9Hz,1H),8.31(d,J＝2.1Hz,1H),7.91–7.76(m,3H),7.72(d,J＝7.9Hz,2H),7.57–7.40(m,2H),5.13(dd,J＝13.3,5.0Hz,1H),4.44(dd,J＝53.3,17.5Hz,2H),4.29(s,2H),3.67-3.57(m,2H),3.01–2.81(m,5H),2.67-2.55(m,1H),2.46–2.35(m,1H),2.11–1.93(m,2H),1.94-1.85(m,2H),1.42-1.27(m,2H).
As shown by 1 H NMR results, A80.HCl contains 2 molecules of hydrochloric acid.
Example IV, test of C-MYC protein degradation Capacity of A80.HCl on transitional bladder cancer cells, prostate cancer cells, ductal breast cancer cells, and breast cancer cells
1. Cell culture and treatment
T24, MDA-MB-231 and T47D cells were cultured in DMEM medium. 5637. C4-2B and DU145 cells were cultured in RPMI 1640 medium. All media contained 10% FBS,100 units of penicillin and 100. Mu.g/mL streptomycin. All cells were cultured in humidified incubator at 37 ℃ and 5% carbon dioxide. Cells were subjected to a conventional mycoplasma infection assay during cell culture, with a monthly assay period.
2. Immunoblotting and immunoprecipitation
Cells treated with different doses of A80.HCl (0-1000 nM) were harvested and lysed with lysis buffer (50 mM Tris-HCl, pH 7.4;150mM NaCl;0.1% NP-40) containing protease inhibitors (cOmplete Mini, roche) and phosphatase inhibitors (cocktail I and II, calbiochem) and centrifuged at 12000rpm for 10min at 4 ℃. The supernatant was collected and quantified by BCA protein quantification. Protein samples were prepared with 5 XSDS loading buffer (250 mM Tris-HCl, pH 6.8, 10% SDS,25mM beta-mercaptoethanol, 30% glycerol and 0.05% bromophenol blue) and boiled for 5 minutes. An equivalent sample of protein (30. Mu.g) was then analysed by SDS-PAGE and transferred to nitrocellulose. Membranes were blocked with 5% milk for 1 hour at room temperature and incubated overnight with antibodies to C-MYC and beta-actin at 4 ℃. The next day, membranes were washed three times with 1 XTBST (20mM Tris,100mM NaCl, and 0.1% Tween-20) and incubated with secondary antibodies for 1 hour at room temperature. The protein bands were visualized using ECL substrate (Bio-Rad). Immunoblots were intensity quantified with Image J software.
The experimental results are shown in FIGS. 2-4 (MYC in the figure refers to C-MYC, MB-231 in the figure refers to MDA-MB-231), and A80.HCl can degrade the expression of C-MYC protein in human bladder transitional cell carcinoma cell line T24, human bladder carcinoma cell line 5637, prostate cancer cell line DU-145, human prostate cancer cell line C4-2B, human breast cancer cell line MDA-MB-231 and human breast duct cancer cell line T47D in a dose-dependent manner. The C-MYC protein of 5637/T24 cells can be degraded by 50nM/40nM respectively to reach more than 50%; in prostate cancer cell lines DU145 and C4-2B cells, 50% of C-MYC degradation was caused by 50nM of A80. HCl. In breast cancer cell lines MB-231 and T47D, when the concentration of the A80.HCl reaches 10nM, the degradation effect of the C-MYC protein can reach more than 80%.
Example five, test of proliferation and cloning inhibition ability of A80.HCl on transitional bladder cancer cells, prostate cancer cells, ductal breast cancer cells, and breast cancer cells
1. Test for ability to inhibit proliferation of cells
Each cell (3000 cells/well) under the different medium conditions of example four 1 was plated in 96-well plates with 100 μl of medium containing 10% serum per well. After 24 hours, cells were treated with different concentrations of A80.HCl or Palbociclib or a combination of A80.HCl and Palbociclib for 24 to 48 hours and cell viability was measured using the CCK-8 kit (CCK-8, dojindo) according to the manufacturer's instructions. The concentrations of A80.HCl and Palbociclib used are shown in Table 5. When A80.HCl and Palbociclib were used in combination, the Palbociclib was used at a concentration consistent with its concentration when used alone, and A80.HCl was used at a concentration of 10nM. All cell viability experiments were performed in triplicate. Absorbance at a wavelength of 450 nm was measured using an Epoch microplate spectrophotometer (BioTek).
TABLE 5A 80. Concentration of HCl, palbociclib used alone
The results of the inhibition of proliferation of each cancer cell by A80.HCl, palbociclib, A80.HCl in combination with Palbociclib are shown in FIGS. 5-7 (MB-231 in the figures refers to MDA-MB-231). From FIGS. 5 and 6, it is clear that A80.HCl can inhibit cell proliferation of transitional cell carcinoma cell line T24, bladder cancer cell line 5637, prostate cancer cell line DU145, C4-2B, breast cancer cell line MDA-MB-231, and ductal breast cancer cell line T47D. As can be seen from FIG. 7, 10nM A80.HCl in combination with the CDK4/6 inhibitor Palbociclib (Palbociclib) has an IC50 value of 3.11. Mu.M and 5.65. Mu.M for inhibition of T24 and 5637, both taken alone, exhibiting a synergistic effect in inhibiting the proliferation of transitional cell bladder cancer, bladder cancer cell lines, and particularly for bladder cancer cell line 5637.
2. Cell cloning experiments
In the medium specified in example four, cells were plated in six well plates (1,000 cells/well) and cultured for 1-2 weeks depending on the size of the colonies. Cells were then fixed with 4% paraformaldehyde for 15min and stained with crystal violet (0.5% w/v) for 30min to calculate cell numbers. Colonies were gently rinsed with running water. Colonies with more than 50 cells were counted. The experimental results are shown in FIGS. 8-11 (MB-231 in the figures refers to MDA-MB-231), and A80.HCl can inhibit the formation of clones of transitional cell carcinoma cell line T24, bladder carcinoma cell line 5637, prostatic cancer cell lines DU145, C4-2B, breast cancer cell line MB-231 and breast duct cancer cell line T47D, and has a statistical difference compared with the DMSO group; the applicant has surprisingly found that the use of a combination of a80.hcl and a CDK4/6 inhibitor Palbociclib significantly reduces the formation of clones of transitional cell carcinoma cell line T24 and bladder carcinoma cell line 5637, and that the effect is superior to that of a80.hcl and Palbociclib alone, and that a significant synergistic effect is exhibited.
Example six, A80.HCl and Palbocicib in combination with human bladder transitional cell carcinoma cells, human bladder carcinoma cell nude mice xenograft tumor growth inhibition experiments
Approximately 5X 10 6 T24 or 5637 cells were suspended in 100. Mu.L of serum-free DMEM medium and mixed with Matrigel (Corning, 354234; 1:1) before injection into the abdomen of male nude mice (10 mice per group). Tumor size was measured every 5 days with calipers and Tumor Volume (TV) was calculated as follows:
TV＝L×W2×0.5
where L is the longest diameter of the tumor and W is the shortest diameter of the tumor.
At tumor volumes up to 100-150mm 3 xenograft mice were randomly selected for grouping, 5 mice per group, four groups, each group given the following table 6:
TABLE 6 mouse dosing regimen
Note that: combination in group 4 refers to Palbociclib administration immediately after administration of a80. Hcl.
Tumor size was measured every 5 days, tumor volume was plotted over time after dosing, and at the end of a dosing course study (30 days), mice were dissected, tumors were removed, photographed and weighed. The results are shown in fig. 12 and 13. Compared with a DMSO control group, when the A80.HCl and the Palbocicib are used independently, the growth of T24 and 5637 tumors can be obviously inhibited, and the capacity of the A80.HCl for inhibiting the growth of the tumors is better than that of the Palbocicib; A80.HCl and Palbociclib are combined, and compared with the single medicines, the combined group shows stronger anti-tumor activity and has obvious difference; the P values of inhibition T24 and inhibition P5637 when combined with A80.HCl and Palbociclib were 0.0048,0.0044, respectively, compared to Palbociclib alone.
In conclusion, a80.Hcl showed significant anti-tumor activity on the bladder transitional cell carcinoma cell line T24, bladder carcinoma cell line 5637 xenograft tumor model at the experimental protocol dose. The combined use of A80.HCl and Palbociclib can further enhance the anti-tumor effect compared with the single drug.

Claims (20)

1. A pharmaceutical composition comprising a protein degradation agent or inhibitor and a CDK4/6 inhibitor; the protein degradation agent or inhibitor can degrade or inhibit any one or more proteins of C-MYC, N-MYC, GSPT1, CK1 alpha and IKZF (1/2/3).
2. The pharmaceutical composition according to claim 1, wherein: the protein degradation agent or inhibitor is a compound with a structure shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer and prodrug thereof;
Wherein,
W is selected from: c (R W)2, c= O, C = S, NH or-N-C 1-6 alkyl;
R W is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
G is selected from: H. a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted with a group selected from the group consisting of: hydroxy, -OPO (OR G)2、-OCORG, carboxy, -OS (O) 1-2RG, sulfonate, each R G is independently selected from H, C 1-4 alkyl;
t 1-T3 is independently selected from: o or S;
A 1-A3 is independently selected from: c (R A)2, each R A is independently selected from H, halogen, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R', -COOR ', -OR', -NR 'R';
q 1-Q4 is independently selected from: CR Q or N;
R Q is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
R 'and R' are independently selected from: H. c 1-15 alkyl optionally substituted with halogen, C 3-6 cycloalkyl;
l 1 represents a linking group;
ring Z represents an optionally substituted heterocycloalkyl group containing at least one N atom as a heteroatom, which is linked to L 2 by N;
l 2 is selected from: a bond, a group represented by the following general structure:
-(CHR1)k-；
-(CHR1)m-O-(CHR1)n-；
-(CHR1)m-N(R1)-(CHR1)n-；
-(CHR1)m-CO-(CHR1)n-；
-(CHR1)m-CO-N(R1)-(CHR1)n-；
-(CHR1)m-N(R1)-CO-(CHR1)n-；
Wherein k is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, m and n are independently selected from: 0.1, 2, 3, 4, 5, 6, each R 1 is independently selected from: H. c 1-6 alkyl optionally substituted with halogen;
cy 1 is selected from: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl or optionally substituted biaryl;
Cy 2 is selected from H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl, or optionally substituted biaryl;
u is selected from 0, 1,2, 3, 4, 5.
3. The pharmaceutical composition according to claim 2, wherein: the compound with the structure shown in the formula (I) is selected from structures shown in A1-A117 or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers and prodrugs thereof:
4. A composition according to claim 3, characterized in that: the compound with the structure shown in the formula (I) is selected from a structure shown in A80 or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers and prodrugs thereof.
5. The composition of claim 4, wherein: the compound with the structure shown in the formula (I) is selected from hydrochloride with the structure shown in A80.
6. The composition of any one of claims 1-5, wherein: the CDK4/6 inhibitor is selected from Palbociclib、Ribociclib、Abemaciclib、SHR6390、Trilaciclib、Flavorpiridol(Alvocidib)、Flavorpiridol HCl、AT7519、AT7519HCl、Milciclib(PHA-848125)、R547、Riviciclib hydrochloride(P276-00)、FN-1501、Dalpiciclib、PF-06873600、CDKI-73、MC180295、G1T38、ON123300、FLX-925、BPI-1178、AG-024322、NSC625987、CGP-82996、AMG925.
7. The composition of claim 6, wherein: the CDK4/6 inhibitor is selected from Palbociclib.
8. The composition of claim 7, wherein: the protein degradation agent or inhibitor is A80 hydrochloride, and the CDK4/6 inhibitor is Palbociclib.
9. Use of a pharmaceutical composition comprising a protein degradation agent or inhibitor and a CDK4/6 inhibitor in the preparation of a medicament for the treatment of cancer; the protein degradation agent or inhibitor can degrade or inhibit any one or more proteins of C-MYC, N-MYC, GSPT1, CK1 alpha and IKZF (1/2/3).
10. Use according to claim 9, characterized in that: the protein degradation agent or inhibitor is a compound with a structure shown in a formula (I) or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer and prodrug thereof;
Wherein,
W is selected from: c (R W)2, c= O, C = S, NH or-N-C 1-6 alkyl;
R W is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
G is selected from: H. a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted with a group selected from the group consisting of: hydroxy, -OPO (OR G)2、-OCORG, carboxy, -OS (O) 1-2RG, sulfonate, each R G is independently selected from H, C 1-4 alkyl;
t 1-T3 is independently selected from: o or S;
A 1-A3 is independently selected from: c (R A)2, each R A is independently selected from H, halogen, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R', -COOR ', -OR', -NR 'R';
q 1-Q4 is independently selected from: CR Q or N;
R Q is selected from: H. halogen, cyano, nitro, C 1-15 alkyl optionally substituted by halogen, C 3-15 cycloalkyl, -CONR 'R ", -COOR', -OR ', -NR' R";
R 'and R' are independently selected from: H. c 1-15 alkyl optionally substituted with halogen, C 3-6 cycloalkyl;
l 1 represents a linking group;
ring Z represents an optionally substituted heterocycloalkyl group containing at least one N atom as a heteroatom, which is linked to L 2 by N;
l 2 is selected from: a bond, a group represented by the following general structure:
-(CHR1)k-；
-(CHR1)m-O-(CHR1)n-；
-(CHR1)m-N(R1)-(CHR1)n-；
-(CHR1)m-CO-(CHR1)n-；
-(CHR1)m-CO-N(R1)-(CHR1)n-；
-(CHR1)m-N(R1)-CO-(CHR1)n-；
Wherein k is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, m and n are independently selected from: 0.1, 2, 3, 4, 5, 6, each R 1 is independently selected from: H. c 1-6 alkyl optionally substituted with halogen;
cy 1 is selected from: optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl or optionally substituted biaryl;
Cy 2 is selected from H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted biaryl, or optionally substituted biaryl;
u is selected from 0, 1,2, 3, 4, 5.
11. Use according to claim 10, characterized in that: the compound with the structure shown in the formula (I) is selected from structures shown in A1-A117 or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers and prodrugs thereof:
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12. Use according to claim 11, characterized in that: the compound with the structure shown in the formula (I) is selected from a structure shown in A80 or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers and prodrugs thereof.
13. Use according to claim 12, characterized in that: the compound with the structure shown in the formula (I) is selected from hydrochloride with the structure shown in A80.
14. Use according to any one of claims 9-13, characterized in that: CDK4/6 inhibitors selected from Palbociclib、Ribociclib、Abemaciclib、SHR6390、Trilaciclib、Flavorpiridol(Alvocidib)、Flavorpiridol HCl、AT7519、AT7519HCl、Milciclib(PHA-848125)、R547、Riviciclib hydrochloride(P276-00)、FN-1501、Dalpiciclib、PF-06873600、CDKI-73、MC180295、G1T38、ON123300、FLX-925、BPI-1178、AG-024322、NSC625987、CGP-82996、AMG925.
15. Use according to claim 14, characterized in that: CDK4/6 inhibitors are selected from Palbociclib.
16. Use according to claim 15, characterized in that: the protein degradation agent or inhibitor is A80 hydrochloride, and the CDK4/6 inhibitor is Palbociclib.
17. Use according to claim 16, characterized in that: the cancer is selected from leukemia, lymphoma, glioblastoma, neuroblastoma, melanoma, multiple myeloma, osteosarcoma, liver cancer, lung cancer, kidney cancer, pancreatic cancer, oral cancer, gastric cancer, esophageal cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, breast cancer, ductal breast cancer, colon cancer, rectal cancer, cervical cancer, ovarian cancer, prostate cancer, bladder cancer, transitional cell bladder cancer, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, small cell lung cancer.
18. Use according to claim 17, characterized in that: the cancer is selected from transitional cell bladder cancer, prostate cancer, breast cancer or ductal breast cancer; preferably transitional cell carcinoma of the bladder or bladder cancer.
19. Use according to claim 18, characterized in that: the protein degradation agent or inhibitor is A80 hydrochloride, and the CDK4/6 inhibitor is Palbociclib; the cancer is transitional cell carcinoma of bladder or bladder cancer.
20. Use according to any one of claims 9-19, characterized in that: the protein degradation agent or inhibitor and CDK4/6 inhibitor are used in a combined administration mode, or the protein degradation agent or inhibitor and CDK4/6 inhibitor are prepared into a compound preparation for administration.
CN202311438245.8A 2022-11-01 2023-11-01 Composition containing protein degradation agent or inhibitor and application thereof Pending CN117982498A (en)

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