WO2019129232A1 - Application of cdk inhibitor and oncolytic virus in preparation of antitumor drug - Google Patents

Abstract

An application of a CDK inhibitor and an oncolytic virus in the preparation of an antitumor drug. A CDK inhibitor can be used in the preparation of an oncolytic virus-based antitumor potentiator. Provided are a pharmaceutical composition comprising the CDK inhibitor and the oncolytic virus, a drug kit comprising the CDK inhibitor and the oncolytic virus, and a use of the CDK inhibitor and the oncolytic virus in the treatment of tumors, particularly the tumors not sensitive to the oncolytic virus.

Description

Application of CDK inhibitors and oncolytic viruses in the preparation of antitumor drugs Technical field

The invention belongs to the field of biomedicine and relates to the application of a combination of a CDK inhibitor and an oncolytic virus in the preparation of an antitumor drug.

Background technique

Oncolytic virus is a type of replicable virus that selectively infects and kills tumor cells without damaging normal cells. Oncolytic virotherapy is an innovative tumor-targeted therapeutic strategy that uses natural or genetically engineered viruses to selectively infect tumor cells and replicate in tumor cells for targeted lysis. Kills the role of tumor cells, but does not damage normal cells.

The M1 virus (Alphavirus M1) belongs to the genus Alphavirus, and has a good application effect in the preparation of antitumor drugs. For example, Chinese invention patent application 201410425510.3 discloses that the M1 virus can selectively cause tumor cell death without affecting normal cell survival, and has a very good application prospect in anti-tumor. However, different tumors have different sensitivities to the M1 virus. For some tumors, when the M1 virus is administered alone, the oncolytic effect is not ideal. For example, as described in the Chinese invention patent application 201410425510.3, when used as an anti-tumor drug, M1 is less effective for colorectal cancer, liver cancer, bladder cancer and breast cancer than pancreatic cancer, nasopharyngeal cancer, prostate cancer and melanoma; Tumor, cervical cancer, and lung cancer are second, while gastric cancer is the least significant. Compounds that screen to increase the therapeutic effect of oncolytic virus tumors are expected to increase the antitumor profile and antitumor strength of oncolytic viruses.

The inventors previously used chrysophanol and its derivatives as anti-cancer synergists for M1 virus. It was found that the survival rate of tumor cells decreased to 39.6% after 50 μM of chrysophanol was combined with (MOI=0.001) M1 virus.

The use of drugs may have some negative effects on the body. However, if the dosage of the drug used can be reduced to a very low level, the negative effects are greatly reduced, and the impact on the body is greatly reduced. This is undoubtedly a good way to reduce the side effects of the drug, and it is also a combination of drugs. Another benefit that can be brought about by improving the efficacy.

However, there are few studies on synergistic drugs for oncolytic viruses, especially for alphaviruses, and most of them work at experimental doses of the μM class.

Summary of the invention

It is an object of the present invention to provide an oncolytic virus anti-tumor synergist.

Another object of the present invention is to provide an oncolytic anti-toxic anti-tumor synergist which acts synergistically at low doses.

Another object of the present invention is to provide an oncolytic virus anti-cancer synergist based on a precise mechanism capable of selectively enhancing the killing effect of oncolytic viruses on tumor cells without affecting normal cells.

Another object of the present invention is to provide a use of a CDK inhibitor for the preparation of an oncolytic antitumor synergist.

Another object of the present invention is to provide an antitumor pharmaceutical composition which allows the oncolytic virus to exert a better antitumor effect.

Another object of the present invention is to provide a safe and effective oncolytic virus potentiating drug against tumors which are insensitive to oncolytic viruses.

The invention achieves the above objects by the following technical solutions:

The inventors found through research and screening that CDK inhibitors unexpectedly enhance the oncolytic effect of oncolytic viruses.

The CDK inhibitor is a substance that inhibits CDK activity, or a substance that degrades CDK, or a genetic tool that lowers CDK levels.

The cell cycle is an important part of the life of a cell. Studies have found that the occurrence and development of a variety of malignant tumors are closely related to the disorder of cell cycle regulation mechanism, so tumors are also considered to be a cell cycle disease. CDK (cyclin-dependent kinase) is an important class of serine/threonine kinases that regulate cell cycle progression. Therefore, CDK inhibitors can block cell cycle and control cell proliferation to have anti-tumor. active. In recent years, CDK inhibitors have become a research hotspot of current anticancer drugs.

The inventors can significantly enhance the oncolytic effect of oncolytic viruses by inhibiting CDK. The inventors used a compound SNS-032 that inhibits CDK activity to cooperate with oncolytic viruses, especially M1 virus, on tumor cells. The results showed that SNS-032 can synergize with oncolytic viruses to enhance antitumor effects.

The present inventors have found for the first time that CDK inhibitors can be used as antitumor synergists/drug resistance reversal agents for oncolytic viruses.

The present invention provides the use of a CDK inhibitor for the preparation of an oncolytic virus anti-tumor synergist/drug reversal agent.

The drug resistance reversal agent means that when some alphaviruses are used as antitumor drugs for treating tumors, some tumors are not sensitive to oncolytic viruses, or these tumors are resistant to oncolytic viruses. The oncolytic virus can be used in combination with a CDK inhibitor (as a drug resistance reversal agent) to reverse the tumor's resistance to the oncolytic virus.

The CDK inhibitor is selected from the group consisting of; preferably, the CDK inhibitor includes, but is not limited to, a compound selected from the group consisting of or a derivative thereof having a CDK inhibitory effect, or a pharmaceutically acceptable salt, solvate thereof, or Isomers, isomers: SNS-032, Dinaciclib, etc. Compounds that inhibit CDK activity. The manner in which the compound is obtained may be selected from, but not limited to, chemical separation or synthesis by itself or from commercial sources.

In a preferred embodiment of the invention, the CDK protein inhibitor is SNS-032, and the structural formula is as shown in Formula 1:

In another preferred embodiment of the invention, the CDK protein inhibitor is Dinaciclib, and the structural formula is as shown in Formula 2:

The CDK inhibitors also include tools for CDK gene expression inhibition, including but not limited to genes, gene silencing, and gene editing or knockout.

As an alternative embodiment, the CDK inhibitor is selected from the group consisting of DNA, RNA, PNA or DNA-RNA-hybrid. They can be single-stranded or double-stranded.

CDK inhibitors may include small inhibitory nucleic acid molecules such as short interfering RNA (siRNA), double stranded RNA (dsRNA), microRNA (miRNA), ribozymes, and small hairpin RNA (shRNA), all of which attenuate or eliminate Expression of CDK protein.

These small inhibitory nucleic acid molecules may include first and second strands that hybridize to each other to form one or more double-stranded regions, each strand having a length of about 18 to 28 nucleotides, and about 18 to 23 nucleotides. The length, or 18, 19, 20, 21, 22 nucleotides in length. In addition, single strands may also comprise regions that are capable of hybridizing to each other to form a double strand, such as in a shRNA molecule.

These small inhibitory nucleic acid molecules may include modified nucleotides while retaining this ability to attenuate or abolish the expression of a CDK protein. Modified nucleotides can be used to improve in vitro or in vivo properties such as stability, activity and/or bioavailability. These modified nucleotides may contain deoxynucleotides, 2'-methyl nucleotides, 2'-deoxy-2'-fluoronucleotides, 4'-trinucleotides, locked nucleic acid (LNA) nucleosides. Acid and/or 2'-O-methoxyethyl nucleotide and the like. Small inhibitory nucleic acid molecules, such as short interfering RNA (siRNA), may also contain 5'- and/or 3'-cap structures to prevent exonuclease degradation.

In some embodiments, a double-stranded nucleic acid consisting of a small suppressor nucleic acid molecule contains a blunt, or overhanging, nucleotide at both ends. Other nucleotides may include nucleotides that result in misalignment, bulging, cycling, or oscillating base pairs. Small inhibitory nucleic acid molecules can be formulated for administration, for example, by liposome encapsulation, or by incorporation into other carriers such as biodegradable polymer hydrogels, or cyclodextrins.

Alternatively, the CDK inhibitor further comprises one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic. Wherein, the antibody may be a monoclonal antibody, a polyclonal antibody, a multivalent antibody, a multispecific antibody (eg, a bispecific antibody), and/or an antibody fragment ligated to the CDK. The antibody may be a chimeric antibody, a humanized antibody, a CDR-grafted antibody or a human-type antibody. The antibody fragment may be, for example, Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), a disulfide-bonded FV (sdFv), or a VL, VH domain. The antibody may be in a conjugated form, for example, in combination with a label, a detectable label, or a cytotoxic agent. The antibody may be a homotypic IgG (eg, IgGl, IgG2, IgG3, IgG4), IgA, IgM, IgE or IgD.

The oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus, Gaeta virus. In a preferred embodiment, the oncolytic virus is selected from the group consisting of an M1 virus, a Gaeta virus, or a combination thereof.

The oncolytic viruses (M1 virus, Gaeta virus, adenovirus, vaccinia virus, measles virus, vesicular stomatitis virus, and herpes simplex virus) according to the present invention may especially refer to existing viruses, but do not exclude Some natural mutations that may occur or viruses that have undergone mutations (natural mutations, mandatory mutations, or selective mutations), genetic modifications, sequence additions or deletions, or partial replacements. The oncolytic viruses described herein include viruses that have undergone the above changes. Preferably, the above changes do not affect the effect of said oncolytic virus as described herein. The CDK inhibitor is a substance (for example, a compound, or an amino acid sequence, a nucleotide sequence, etc.) or a tool which can knock down or affect the expression of a CDK gene or decrease the amount of a CDK protein or a protein. A person skilled in the art may modify, replace, change, etc. the inhibitory compound or the gene tool, but the CDK inhibitor belonging to the present invention belongs to the homologous substance of the above substances, compounds or tools as long as the above-mentioned action for inhibiting CDK is exerted. replace.

In some embodiments, the alphavirus is the M1 virus deposited under the accession number CCTCC V201423 (as deposited with the China Center for Type Culture Collection, deposited on July 17, 2014). As a virus most likely derived from the same strain, Genbank Accession No. EF011023 records a sequence of M1. The Gita virus is a virus having a homology of up to 97.8% (Wen et al. Virus Genes. 2007; 35(3): 597-603) with the M1 virus, and the two have a high identity, and the M1 virus is also somewhat The literature is classified as a Gaetavirus. Both can be expected to have similar efficacy. A single alphavirus strain can also be administered. In other embodiments, a variety of strains and/or types of alphaviruses can also be used.

The invention also provides a pharmaceutical composition for treating a tumor comprising a CDK inhibitor and an oncolytic virus. The invention also provides a pharmaceutical kit for treating a tumor comprising a CDK inhibitor or a derivative thereof or a combination thereof, and an oncolytic virus. The drug kit differs from the composition in that the CDK inhibitor is different from the oncolytic virus in the form of a separate package (eg, a pill, or a capsule, or a tablet or vial containing a CDK inhibitor; additional pills, Or capsules, or tablets or vials containing oncolytic viruses). In some embodiments, an oncolytic virus, a CDK inhibitor, and a combination of an oncolytic virus and a CDK inhibitor may also contain one or more adjuvants. The adjuvant refers to an ingredient which can assist the therapeutic effect of the drug in the composition of the drug. The drug kit can also contain individually packaged CDK inhibitors as well as individually packaged oncolytic viruses. The CDK inhibitor in the drug kit, and the administration of the oncolytic virus, may be administered simultaneously or in any anterior-posterior sequence, such as administration of a CDK inhibitor prior to the oncolytic virus, or administration of a CDK inhibitor following the oncolytic virus, or Both are administered simultaneously. In various embodiments, the patient can be a mammal. In some embodiments, the mammal can be a human.

The CDK inhibitors include, but are not limited to, compounds that inhibit CDK protein activity, such as SNS-032 (Formula 1) or Dinaciclib (Formula 2). Or for CDK gene expression inhibition tools, including but not limited to gene interference, gene silencing, and gene editing or knockout tools. As a preferred embodiment of the present invention, the CDK inhibitor is SNS-032.

The oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus and Gaeta virus. In a preferred embodiment, the oncolytic virus is selected from at least one of an M1 virus and a Gata virus.

In the composition or the pharmaceutical kit, the ratio of SNS-032 or Dinaciclib to the oncolytic virus is optionally: 0.005 to 200 mg: 10 ³ to 10 ⁹ PFU; preferably 0.005 to 50 mg: 10 ⁴ to 10 ⁹ PFU; further preferably 0.005 to 20 mg: 10 ⁵ to 10 ⁹ PFU.

Preferably, the dosage is: SNS-032 or Dinaciclib is used in the range of 0.01 mg/kg to 200 mg/kg, and the oncolytic virus uses a titer of MOI from 10 ³ to 10 ⁹ (PFU/kg); preferably SNS-032 or Dinaciclib is used. The range is from 0.05 mg/kg to 200 mg/kg, while the oncolytic virus uses a titer of MOI from 10 ⁴ to 10 ⁹ (PFU/kg); more preferably SNS-032 or Dinaciclib is used from 0.05 mg/kg to 20 mg/kg. At the same time, the oncolytic virus uses a titer of MOI from 10 ⁵ to 10 ⁹ (PFU/kg).

In one embodiment, the oncolytic virus is selected from the group consisting of an M1 virus, a Gata virus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus. Preferably, the oncolytic virus is at least one of an M1 virus and a Gata virus.

In one embodiment, the tumor is a solid tumor or a hematoma. In one embodiment, the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer. In a preferred embodiment, the tumor is a tumor that is insensitive to oncolytic viruses. In a more preferred embodiment, the tumor is a tumor that is insensitive to Ml oncolytic virus.

As an alternative embodiment, the SNS-032 or Dinaciclib provided by the present invention may be an injection, a tablet, a capsule, a patch, a kit, or the like. As a preferred embodiment, the synergistic drug of the present invention is an injection; preferably, intravenous injection can be employed.

As a further preferred embodiment of the invention:

The present inventors have found that CDK inhibitors, especially SNS-032, can increase the antitumor effect of oncolytic viruses to enhance the therapeutic effectiveness of oncolytic viruses as antitumor drugs. Cytological experiments show that the combination of M1 virus and SNS-032 can significantly cause morphological lesions of tumor cells, thereby significantly enhancing the inhibition of tumor cells.

We combined SNS-032 and M1 virus on human hepatocellular carcinoma Hep3B strain, and unexpectedly found that the combination of antiviral compound SNS-032 and M1 virus significantly increased tumor cell morphology and significantly reduced tumor cell survival rate. For example, in one embodiment of the present invention, when the M1 virus (MOI=0.001) is treated with liver cancer cells alone, the tumor cell survival rate is 79.9%, and when the liver cancer cells are treated with 50 nM SNS-032 alone, the tumor cell survival rate remains. Up to 90.0%, when combined with 50 nM SNS-032 and the same MOI M1 virus, the tumor cell survival rate dropped significantly to 47.6%. Compared with the anti-tumor effect of the M1 virus alone, the oncolytic effect was significantly improved when SNS-032 was combined with M1. It can be seen that the greatly enhanced oncolytic effect of SNS-032 in combination with M1 is due to the synergistic mechanism between SNS-032 and M1 virus, and does not simply act through the anti-tumor mechanism of SNS-032.

The oncolytic virus synergist used in the present invention also has a feature that it can obtain an effect of enhancing the effect of oncolytic virus at an extremely low application dose. For example, although the dose is so low (eg, as low as 50 nM), the killing rate of SNS-032 on cancer cells is almost negligible (hepatocellular carcinoma cell survival rate is still as high as 90.0%). However, when used in combination with alphavirus (MOI = 0.001) at such a low dose, tumor cell survival rate dropped significantly to 47.6%. The use of very low doses can greatly reduce other toxic side effects that may be caused by the drug itself, and the effect of the drug on the body is reduced. This is very important for patients who are undergoing cancer treatment.

DRAWINGS

Figure 1 SNS-032 combined with M1 virus treatment significantly reduced the survival rate of human hepatocellular carcinoma cell line Hep3B.

Detailed ways

The invention is further described in the following embodiments, but the embodiments of the present invention are not limited to the following embodiments, and equivalent changes or modifications made in accordance with the principles and concepts of the present invention are considered to be within the scope of the present invention.

The materials and experimental methods employed in the present invention are conventional materials and methods, unless otherwise specified.

"Selected from" in the specification is connected to the selected object, and can be understood as, for example, "X is selected from: A, B, C, ..., E" or "X is selected from: A, B, C, ... and One or more of E, etc., can be understood to include X, one of A, B, C, ... E, or any combination of the two, or any combination of the plurality. It is not excluded at this time that X also includes some other categories of substances.

In addition to the specific CDK inhibitors mentioned above, the inhibitors of the present invention may also be selected from CDK inhibitors which are well known in the art, or substances which have been found to have CDK inhibition by subsequent studies.

Example 1 SNS-032 combined with M1 virus significantly reduced the survival rate of human hepatocellular carcinoma Hep3B material:

Human hepatocellular carcinoma Hep3B (purchased from ATCC), M1 virus (Accession No. CCTCC V201423), high glucose DMEM medium (purchased from Corning), automatic enzyme-linked detection microplate reader.

method:

a) Inoculation of cells, administration: Select logarithmic growth phase cells, DMEM complete medium (containing 10% fetal bovine serum, 1% double antibody) to make cell suspension, with a density of 4 × 10 ³ /well per well Inoculate in a 96-well culture plate. After 12 hours, the cells were fully adherent. The experiment was divided into control group, SNS-032 group alone, M1 infection group and SNS-032/M1 combination group. The doses used were: M1 virus (MOI = 0.001) infected cells; SNS-032 was 50 nM.

b) MTT and intracellular succinate dehydrogenase reaction: when cultured to 48h, add 20μl (5mg/ml) of MTT to each well and continue to incubate for 4 hours. At this time, microscopically formed granular particles can be observed in living cells. Blue-purple nails crystallize.

c) Dissolving the formazan granules: carefully aspirate the supernatant, add DMSO 100 μl/well to dissolve the crystals, shake on a micro-vibrator for 5 min, and then measure the optical density (OD value) of each well with a wavelength of 570 nm on an enzyme-linked detector. ). Cell viability = OD value of the drug-treated group / OD value of the control group × 100%.

result:

As shown in Figure 1, M1 virus (MOI=0.001) treatment alone had a lower survival rate inhibition effect on tumor cell Hep3B, tumor cell survival rate reached 79.9%, and 50NM SNS-032 treatment group tumor cell survival rate was still as high as 90.0. %, however, when the same 50 nM SNS-032 was combined with the M1 virus (MOI=0.001) (SNS-032+M1), the tumor cell survival rate dropped significantly to 47.3%.

Claims (9)

1. The use of CDK inhibitors in the preparation of oncolytic virus anti-tumor synergists or drug resistance reversal agents;

   Preferably, the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus;

   More preferably, the alphavirus is selected from at least one of an M1 virus and a Gata virus.
2. The use according to claim 1, wherein the CDK inhibitor is a substance that inhibits CDK activity, or a substance that degrades CDK, or a genetic tool that lowers CDK levels, or any combination thereof;

   Preferably, the CDK inhibitor is selected from the group consisting of compounds; more preferably, the CDK inhibitor is selected from the following compounds or derivatives thereof having CDK inhibitory effects, or pharmaceutically acceptable salts, solvates thereof, and Isomers, isomers: SNS-032, Dinaciclib;

   More preferably, the structural formula of the SNS-032 is as shown in Equation 1:

   

   More preferably, the structural formula of the Dinaciclib is as shown in Equation 2:

   

   Or preferably, the CDK inhibitor is selected from one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic;

   Or preferably, the CDK inhibitor is a gene interference, gene silencing, gene editing or gene knockout material;

   Or preferably, said CDK inhibitor is selected from one or more of the group consisting of: DNA, RNA, PNA and DNA-RNA-hybrid;

   More preferably, the CDK inhibitor is selected from one or more of the group consisting of: siRNA, dsRNA, miRNA, shRNA, and ribozyme;

   More preferably, the CDK inhibitor is a tumor targeting CDK inhibitor.
3. A pharmaceutical composition for treating a tumor comprising:

   (a) a CDK inhibitor;

   The CDK inhibitor is a substance that inhibits CDK activity, or a substance that degrades CDK, or a genetic tool that lowers CDK levels, or any combination thereof;

   Preferably, the CDK inhibitor is selected from the group consisting of compounds; more preferably, the CDK inhibitor is selected from the following compounds or derivatives thereof having CDK inhibitory effects, or pharmaceutically acceptable salts, solvates thereof, and Isomers, isomers: SNS-032, Dinaciclib;

   More preferably, the structural formula of the SNS-032 is as shown in Equation 1:

   

   More preferably, the structural formula of the Dinaciclib is as shown in Equation 2:

   

   Or preferably, the CDK inhibitor is selected from one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic;

   Or preferably, the CDK inhibitor is a gene interference, gene silencing, gene editing or gene knockout material;

   Or preferably, said CDK inhibitor is selected from one or more of the group consisting of: DNA, RNA, PNA and DNA-RNA-hybrid;

   More preferably, the CDK inhibitor is selected from one or more of the group consisting of: siRNA, dsRNA, miRNA, shRNA, and ribozyme;

   More preferably, the CDK inhibitor is a tumor targeting CDK inhibitor;

   (b) an oncolytic virus; the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus;

   Preferably, the alphavirus is selected from at least one of an M1 virus and a Gata virus.
4. A medicine kit containing:

   (a) a CDK inhibitor;

   The CDK inhibitor is a substance that inhibits CDK activity, or a substance that degrades CDK, or a genetic tool that lowers CDK levels, or any combination thereof;

   Preferably, the CDK inhibitor is selected from the group consisting of compounds; more preferably, the CDK inhibitor is selected from the following compounds or derivatives thereof having CDK inhibitory effects, or pharmaceutically acceptable salts, solvates thereof, and Isomers, isomers: SNS-032, Dinaciclib;

   More preferably, the structural formula of the SNS-032 is as shown in Equation 1:

   

   More preferably, the structural formula of the Dinaciclib is as shown in Equation 2:

   

   Or preferably, the CDK inhibitor is selected from one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic;

   Or preferably, the CDK inhibitor is a gene interference, gene silencing, gene editing or gene knockout material;

   Or preferably, said CDK inhibitor is selected from one or more of the group consisting of: DNA, RNA, PNA and DNA-RNA-hybrid;

   More preferably, the CDK inhibitor is selected from one or more of the group consisting of: siRNA, dsRNA, miRNA, shRNA, and ribozyme;

   More preferably, the CDK inhibitor is a tumor targeting CDK inhibitor;

   (c) an oncolytic virus; the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus;

   Preferably, the alphavirus is selected from at least one of an M1 virus and a Gata virus;

   Preferably, the pharmaceutical kit comprises a separately packaged CDK inhibitor and a separately packaged oncolytic virus.
5. The use of a combination of a CDK inhibitor and an oncolytic virus for the preparation of a medicament for treating tumors;

   The oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus;

   Preferably, the alphavirus is selected from at least one of an M1 virus and a Gata virus;

   The CDK inhibitor is a substance that inhibits CDK activity, or a substance that degrades CDK, or a genetic tool that lowers CDK levels;

   Preferably, the CDK inhibitor is selected from the group consisting of compounds; more preferably, the CDK inhibitor is selected from the following compounds or derivatives thereof having CDK inhibitory effects, or pharmaceutically acceptable salts, solvates thereof, and Isomers, isomers: SNS-032, Dinaciclib;

   More preferably, the structural formula of the SNS-032 is as shown in Equation 1:

   

   More preferably, the structural formula of the Dinaciclib is as shown in Equation 2:

   

   Or preferably, the CDK inhibitor is selected from one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic;

   Or preferably, said CDK inhibitor is selected from the group consisting of a gene interference, a gene silencing, a gene editing or a gene knockout material;

   Or preferably, said CDK inhibitor is selected from one or more of the group consisting of: DNA, RNA, PNA and DNA-RNA-hybrid;

   More preferably, the CDK inhibitor is selected from one or more of the group consisting of: siRNA, dsRNA, miRNA, shRNA, and ribozyme;

   More preferably, the CDK inhibitor is a tumor targeting CDK inhibitor.
6. The composition of claim 3 wherein said composition further comprises a pharmaceutically acceptable carrier; said carrier is preferably selected from the group consisting of lyophilized powders, injections, tablets, capsules, kits or patches.
7. The use/composition/drug set according to any of claims 1-6, characterized in that the CDK inhibitor is SNS-032 and/or Dinaciclib.
8. The composition/pharmaceutical kit according to any one of claims 3, 4, 6 or 7, wherein the ratio of the SNS-032 or Dinaciclib to the oncolytic virus is 0.005 to 200 mg: 10 ³ to 10 ⁹ PFU; preferably 0.005 to 50 mg: 10 ⁴ to 10 ⁹ PFU; further preferably 0.005 to 20 mg: 10 ⁵ to 10 ⁹ PFU;

   Further preferably, the dosage used is: SNS-032 or Dinaciclib, the use range is from 0.01 mg/kg to 200 mg/kg, and the oncolytic virus uses a titer of MOI from 10 ³ to 10 ⁹ (PFU/kg); preferably SNS-032 Or Dinaciclib is used in the range of 0.05 mg/kg to 200 mg/kg, while the oncolytic virus uses a titer of MOI from 10 ⁴ to 10 ⁹ (PFU/kg); more preferably SNS-032 or Dinaciclib is used in the range of 0.05 mg/kg to 20 mg/kg, while the oncolytic virus uses a titer of MOI from 10 ⁵ to 10 ⁹ (PFU/kg).
9. The use/composition/drug set according to any one of claims 1 to 8, wherein the tumor is a solid tumor or a hematoma; preferably, the solid tumor is liver cancer, colorectal cancer, bladder cancer , breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer or stomach cancer;

   Or preferably, the tumor is a tumor that is insensitive to oncolytic viruses;

   More preferably, the tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer or gastric cancer which are insensitive to oncolytic virus. .

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