ADP-ribose binding peptides having anticancer activity and their uses

Abstract

The present invention relates to an ADP (adenosine diphosphate)-ribose binding peptide having anticancer activity, specifically, to an ADP-ribose binding peptide having a specific amino acid sequence and its variant, and to a pharmaceutical composition for preventing or treating cancer and an anticancer adjuvant pharmaceutical composition containing the same as an active ingredient. The ADP-ribose binding peptide of the present invention accumulates ADP-ribose in cancer cells, leading to the death of cancer cells by disrupting the balance of cells, and has an excellent anticancer effect without showing toxicity to normal cells. When administered in combination with other anticancer drugs or during radiation anticancer therapy, it enhances the reactivity to anticancer drugs and radiation therapy, and has an extremely excellent effect as an anticancer adjuvant.

Description

[Technical field]

[0001] The present invention relates to an ADP (adenosine diphosphate)-ribose-binding peptide having anti-cancer activity, specifically, an ADP-ribose-binding peptide having a specific amino acid sequence and a variant thereof, and a pharmaceutical composition for preventing or treating cancer and a pharmaceutical composition for adjuvant anti-cancer therapy, each containing the same as an active ingredient. [Background technology]

[0002] PARylation (poly ADP-ribosylation) is a post-translation modification process in which ADP-ribose polymers (poly(adenosine diphosphate-ribose)) are covalently attached to proteins by PAR polymerase. PARylation produces a polymeric ADP-ribose chain, which can induce unique intracellular biochemical actions that are not small molecular-dimensional modifications such as acetylation or methylation, and do not show the same forms as ubiquitination or SUMOylation. The balance of PARylation plays an important role in DNA damage repair, transcription regulation, chromatin structure modification, oxidation / reduction homeostasis, various intracellular signal transduction, non-membrane structure formation, host-pathogen interactions, and RNA metabolism regulation (Juan et al., Cancers, 2020, 12(3):739).

[0003] PARylation is involved in the pathogenesis of systemic diseases including cancer, viral infection and neurodegeneration. In particular, PARylation is derived from the activation of PARP-1, and the anticancer efficacy of methods that inhibit PARP-1 activity to target ovarian, prostate, breast and other cancers is already well known (J Mateo et al., Ann Oncol., 2019, 30(9):1437).

[0004] Information on the biochemical mechanisms associated with PARylation-mediated cell death has become available relatively recently, and activation of PARylation can typically induce cell death through three major pathways (Rebecca Gupte et al., Genes Dev. 2017, 31(2):101).

[0005] NAD + Depletion of NAD can impair cellular metabolism, especially the oxidative phosphorylation process, which occurs during cellular energy crisis (ATP depletion). + It has been proposed that the enzyme may consume the cytosolic acid, and that a subsequent effect of this action may be cell death.

[0006] In addition, PAR polymers released from the nucleus after DNA repair can release apoptosis-inducing factors bundled in the mitochondrial membrane in the cytoplasm, activating a pathway that recruits apoptosis-inducing factors into the nucleus. When the apoptosis-inducing factors are transferred to the nucleus, they mediate large-scale DNA fragmentation, inducing cell death. Energy depletion and apoptosis-inducing factors due to PARylation are known to be related to PAR signaling that controls protein kinase-phosphatase pathways such as the PI3K-Akt pathway or the MAP kinase pathway, and such PAR-dependent cell death processes contribute to a considerable level of complexity in the death mechanism.

[0007] Although the biochemical mechanism is still unclear, it has been reported that PARP-1 can degrade itself through autoPARylation, inducing cell death. However, cancer cells can cleverly circumvent this process by activating various proteolytic enzymes to degrade excess PAR polymers that are involved in various biochemical functions required for cancer survival.

[0008] Therefore, contrary to existing attempts to inhibit PARylation such as PARP-1 inhibitors, activating PARylation or inhibiting the degradation of PAR polymers may also be a strategy for discovering effective anti-cancer therapies. In particular, activating PARylation or inhibiting the degradation of PAR polymers may be very promising targets in cancer cell-specific regions that undergo metabolic processes different from those of normal cells. Summary of the Invention [Problem to be solved by the invention]

[0009] As a result of extensive efforts to develop a novel anti-cancer drug, the present inventors have confirmed that a peptide having a novel amino acid sequence of the present invention can bind to ADP-ribose, ultimately preventing ADP-ribose or PAR polymer from being utilized by various intracellular degradative enzymes and signaling proteins, thereby overactivating PARylation and disrupting the degradative process of PAR polymerase, and as a result of this disruption, it can induce the death of cancer cells and exhibit revolutionary anti-cancer efficacy, thereby completing the present invention. [Means for solving the problem]

[0010] One object of the present invention is to provide an ADP (adenosine diphosphate)-ribose binding peptide having any one amino acid sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:14.

[0011] Another object of the present invention is to provide a polynucleotide encoding the peptide.

[0012] It is still another object of the present invention to provide a vector and a transformant containing the polynucleotide.

[0013] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, an adjunctive anti-cancer pharmaceutical composition for enhancing responsiveness to a second anti-cancer drug, and an adjunctive anti-cancer pharmaceutical composition for enhancing responsiveness to radiation anti-cancer therapy, each of which comprises the peptide or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0014] Yet another object of the present invention is to provide a use of the peptide or a pharma- ceutical acceptable salt thereof for the prevention or treatment of cancer, and a method for the prevention or treatment of cancer, comprising a step of administering the peptide or a pharma- ceutical acceptable salt thereof to an individual in need thereof. Effect of the Invention

[0015] The ADP-ribose-binding peptide of the present invention accumulates ADP-ribose in cancer cells, thereby disrupting the cellular balance and causing the death of the cancer cells, and at the same time has excellent anti-cancer effects without causing toxicity to normal cells. When administered in combination with other anti-cancer drugs or during radiation anti-cancer therapy, it enhances responsiveness to anti-cancer drugs and radiation therapy, and is also extremely effective as an anti-cancer adjuvant. [Brief description of the drawings]

[0016] [Figure 1] 1 shows the intracellular poly ADP-ribose levels after different cancer cells were treated with peptides of SEQ ID NOs: 1 to 4 at different concentrations. [Diagram 2] 1 shows the intracellular poly ADP-ribose levels after different cancer cells were treated with peptides of SEQ ID NOs: 5 to 8 at different concentrations. [Diagram 3] 1 shows the intracellular poly ADP-ribose levels after different cancer cells were treated with peptides of SEQ ID NOs: 9 to 12 at different concentrations. [Figure 4] 1 shows the intracellular poly ADP-ribose levels after different cancer cells were treated with peptides of SEQ ID NO:13 and 14 at different concentrations. [Diagram 5]The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 1, SEQ ID NO: 15, SEQ ID NO: 2, and SEQ ID NO: 16. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 6] The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 3, SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 18. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 7] The figures show the results of examining the viability of different cancer cells after treatment with peptides of SEQ ID NO: 5, SEQ ID NO: 19, SEQ ID NO: 6, and SEQ ID NO: 20. The upper figure shows a photograph of the cells, and the lower graph shows the cell viability. [Figure 8] The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 7, SEQ ID NO: 21, SEQ ID NO: 8, and SEQ ID NO: 22. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 9] The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 9, SEQ ID NO: 23, SEQ ID NO: 10, and SEQ ID NO: 24. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 10] The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 11, SEQ ID NO: 25, SEQ ID NO: 12, and SEQ ID NO: 26. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 11] The figures show the results of examining the viability of different cancer cells after treating them with peptides of SEQ ID NO: 13, SEQ ID NO: 27, SEQ ID NO: 14, and SEQ ID NO: 28. The upper figure shows a photo of the cells, and the lower graph shows the cell viability. [Figure 12]1 shows the results of examining the viability of different cancer cells after treating them with each of the peptides of SEQ ID NO: 15 to SEQ ID NO: 28. [Figure 13] The figure shows cell viability after treatment of different cancer cells with bevacizumab (left) or osimertinib (right), either alone or in combination with peptides of SEQ ID NO:1 to SEQ ID NO:14. [Figure 14] The graph shows cell viability after treatment of different cancer cells with gemcitabine (left) or docetaxel (right), either alone or in combination with peptides of SEQ ID NO:15 to SEQ ID NO:28. [Figure 15] 1 shows the cell survival rates after irradiation of different cancer cells with 2 Gy of radiation alone or in combination with the peptides of SEQ ID NO:1 to SEQ ID NO:14. [Figure 16] FIG. 1 shows the cell viability of different cancer cells after irradiation with 2 Gy of radiation alone or in combination with the peptides of SEQ ID NO:15 to SEQ ID NO:28. [Figure 17] 1 shows the change in tumor volume over time after peptides of SEQ ID NO: 15 to SEQ ID NO: 28 were subcutaneously administered to a tumor-implanted animal model. [Figure 18] 1 shows photographs of tumor tissues observed after subcutaneous administration of peptides of SEQ ID NO: 15 to SEQ ID NO: 28 in a tumor-implanted animal model. [Figure 19] FIG. 1 shows the change in tumor volume over time after oral administration of peptides of SEQ ID NO: 1 to SEQ ID NO: 14 to a tumor-implanted animal model. [Figure 20] 1 shows photographs of tumor tissues observed in a tumor-implanted animal model after oral administration of peptides of SEQ ID NO: 1 to SEQ ID NO: 14. [Figure 21] Representatively, the toxicity of the peptide of SEQ ID NO: 7 to normal cells (CCD-18Co) is evaluated. [Figure 22] Representatively, the toxicity of the peptide of SEQ ID NO: 7 to normal cells (HDPC) is evaluated. [Figure 23] 7 shows the structure of the peptide of SEQ ID NO:7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of various elements disclosed in the present invention belong to the scope of the present invention. In addition, the specific description described below is not intended to limit the scope of the present invention.

[0018] One embodiment of the present invention for achieving the above object is an ADP (adenosine diphosphate)-ribose binding peptide having any one amino acid sequence selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:14.

[0019] In the present invention, the term "ADP-ribose" is used as a concept including both isolated ADP-ribose itself and ADP-ribose polymer (poly ADP-ribose), and "ADP-ribose binding peptide" means all peptides having activity of binding to ADP-ribose or ADP-ribose polymer and inhibiting its decomposition. In the present invention, the peptide is not only formed by peptide bonds between the amino acids constituting it, but also includes all types of peptide analogs, derivatives, and other modifications having partially modified forms to improve properties such as stability and efficacy in terms of protein pharmaceuticals.

[0020] The present inventors have focused on the fact that, unlike the many reported anti-cancer efficacies of PARP-1 inhibitors, which are based on the inhibition of PARylation (poly ADP-ribosylation), the anti-cancer effects can also be expected through the activation of PARylation or inhibition of the degradation of PAR polymers. In particular, since cancer cells divide at a faster rate than normal cells and have active metabolic activity, it was expected that by overactivating PARylation or inhibiting the degradation of PAR polymers, cancer cells could be specifically killed without any particular effect on normal cells that do not overactivate PARylation.

[0021] The ADP (adenosine diphosphate)-ribose binding peptides having any one of the amino acid sequences selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 14 (Table 1) of the present invention are all derived from the WWE domain. The WWE domain is a globular domain conserved in many proteins such as deltex, Trip12, and poly-ADP-ribose polymerase homologues, and was named after the most conserved residue in the domain (L. Aravind, TRENDS in Biochemical Sciences, 2001, 26(5):273). It is known that some proteins having a WWE domain have an ADP-ribose binding motif in the domain. It has been reported that the WWE domain of intracellular enzymes mainly binds to ADP-ribose to induce its decomposition. In other words, the binding of a specific enzyme to PAR or ADPR through the WWE domain is believed to be important for the survival of cancer cells (PNAS August 23, 2011 108(34)14103-14108).

[0022] However, there has been no report that, when a portion of the WWE domain is produced as an isolated peptide and treated with cells, as in the present invention, ADP-ribose degradation is inhibited, intracellular ADP-ribose accumulates, and an excellent anti-cancer effect is ultimately achieved.

[0023] In a specific embodiment of the present invention, fragments of the WWE domain present in various proteins were synthesized and their anti-cancer activity was examined. As a result, it was confirmed that when various types of cancer cells were treated with the ADP-ribose binding peptides (SEQ ID NOs: 1 to 14) of Examples 1 to 14, the level of ADP-ribose in the cancer cells significantly increased (FIGS. 1 to 4). Furthermore, it was confirmed through in vitro experiments that the treatment with the peptides disrupted the balance of ADP-ribose in the cells, suppressing the growth of the cancer cells and almost killing them (FIGS. 5 to 11). It was also confirmed through tumor transplant animal models that the growth of tumor tissues in vivo was rapidly reduced when the ADP-ribose binding peptides of Examples 1 to 14 were administered subcutaneously or orally (FIGS. 19 and 20).

[0024] In another specific embodiment of the present invention, the peptide of SEQ ID NO: 7 was treated with normal cells to evaluate the cytotoxicity of the normal cells, and it was confirmed that the peptide did not show any toxicity to the normal cells (FIGS. 21 and 22).

[0025] Therefore, the ADP-ribose binding peptides of SEQ ID NOs: 1 to 14 of the present invention have extremely excellent anticancer effects regardless of the type of cancer and do not exhibit any cytotoxicity to normal cells, and therefore can be usefully used as compositions for preventing or treating cancer.

[0026] The ADP-ribose binding peptide is not only a peptide having any one of the amino acid sequences of SEQ ID NOs: 1 to 14, but also any sequence in which one or more amino acids are added, substituted or combined with these sequences, so long as it falls within the equivalent range, falls within the scope of the present invention.

[0027] For example, as long as a peptide has at least 80% or more, 90% or more, 95% or more, 97% or more, or 99% or more homology with a peptide having any one of the amino acid sequences of SEQ ID NOs: 1 to 14 of the present invention and exhibits efficacy corresponding to the peptide consisting of any one of the amino acid sequences of SEQ ID NOs: 1 to 14, i.e., ADP-ribose binding activity and anti-cancer activity, it is obvious that the peptide is included within the scope of the present invention even if it has an amino acid sequence in which a partial sequence is added, substituted, or combined with the amino acid sequence of SEQ ID NOs: 1 to 14.

[0028] In addition, meaningless additions to or from the amino acid sequence, naturally occurring mutations, or silent mutations thereof may also be included within the scope of the present invention, so long as they have activity corresponding to a peptide consisting of any one of the amino acid sequences of SEQ ID NOs: 1 to 14.

[0029] In the present invention, the term "homology" refers to the degree of identity with a given amino acid sequence or nucleotide sequence, and may be expressed as a percentage. In the present specification, a homologous sequence having the same or similar activity as a given amino acid sequence or nucleotide sequence is expressed as "% homology". For example, it can be confirmed by using standard software, specifically BLAST2.0, which calculates parameters such as score, identity, and similarity, or by comparing sequences through Southern hybridization experiments under defined stringent conditions, and the defined appropriate hybridization conditions are within the scope of the relevant technology and can be determined by methods well known to those skilled in the art (e.g., J. Sambrook et al., Molecular Cloning, A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory press, Cold Spring Harbor, New York, 1989; FMAusubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., New York).

[0030] In addition, the peptide of the present invention may include modifications such as chemical derivatization of one or more amino acids constituting the peptide in order to further improve desired properties, and it will be obvious to those skilled in the art that such modifications fall within the scope of the present invention as long as they have the same anticancer activity as the peptide of the present invention. The derivatization may include, but is not limited to, acetylation, hydroxylation, methylation, amidation, pegylation, and the addition of carbohydrate or lipid moieties, cofactors, etc.

[0031] In a specific embodiment of the present invention, the peptide may be used in a form fused with a cell-penetrating peptide to enhance cell permeability. That is, the ADP-ribose binding peptide may further include a cell-penetrating peptide at the N-terminus, C-terminus, or both termini. In this case, a linker may further be included between the ADP-ribose binding peptide and the cell-penetrating peptide, which may be appropriately performed by those skilled in the art.

[0032] In the present invention, the term "cell-penetrating peptide" refers to a peptide having a property of promoting intracellular uptake / absorption of various substances such as nanoparticles, compounds, DNA, proteins, etc. Specifically, the cell-penetrating peptide may be TAT, maurocalcine, penetratin, poly-arginine-derived peptide, Antennapedia, Transportan, VP22, Hph-1, poly-arginine, R11 (R9), Pep-1, HP4, LAH4, Vetofusing-1, signal sequence-based peptide, or amphipathic peptide, but is not limited thereto, and may be appropriately selected by those skilled in the art as long as it can promote intracellular transport of the ADP-ribose binding peptide of the present invention.

[0033] In a specific embodiment of the present invention, the cell-permeable peptide TAT was fused to the N-terminus of the ADP-ribose binding peptides of SEQ ID NOs: 1 to 14 of the present invention, and their anticancer activity was evaluated (SEQ ID NOs: 15 to 24, Table 2). As a result, it was confirmed that the ADP-ribose binding peptides have anticancer activity superior to that of the ADP-ribose binding peptides used alone (FIGS. 5 to 12, 17 and 18). Therefore, not only the ADP-ribose binding peptides of SEQ ID NOs: 1 to 14 of the present invention, but also the peptides fused with cell-permeable proteins can be very usefully used as compositions for preventing or treating cancer.

[0034] Furthermore, those skilled in the art can appropriately modify the ADP-ribose binding peptide of the present invention to apply it depending on the type of cell-penetrating peptide used. That is, even when the ADP-ribose binding peptide of the present invention is used by fusing it to a cell-penetrating peptide, it is not limited to the amino acid sequence presented in the present invention, and can be used by adding / substituting / removing the amino acid sequence in a form appropriate for the application of the cell-penetrating peptide within a range obvious to those skilled in the art, i.e., within an equivalent range.

[0035] In addition, the ADP-ribose binding peptides of the present invention may be used with reagents known in the art that can deliver proteins to cells or enhance delivery efficiency to enhance cell permeability. TM (Active motif, Cat.30025), Xflect TM (Takara, Cat.631324), Pierce TM (ThermoFisher Scientific, Cat.89850), ProteoJuice TM (Merck, Cat. 71281), PULSin TMThe present invention is not limited to the above examples, and includes not only commercially available reagents such as (Poylplus transfection) but also all other non-commercial reagents, as long as they can deliver the ADP-ribose binding peptide of the present invention to cells.

[0036] Another aspect of the present invention is a polynucleotide encoding the ADP-ribose binding peptide.

[0037] Yet another aspect of the present invention is a vector comprising the polynucleotide.

[0038] Yet another aspect of the present invention is a transformant comprising the above polynucleotide.

[0039] The ADP-ribose binding peptide is as explained above.

[0040] The polynucleotide may have a nucleotide sequence encoding the ADP-ribose binding peptide of the present invention, or a nucleotide sequence having at least 80% or more, 90% or more, 95% or more, 97% or more, or 99% or more homology thereto. If a polypeptide translated from the polynucleotide exhibits an activity corresponding to the ADP-ribose binding peptide of the present invention, the addition of meaningless sequences to the 5'- and / or 3'-end of the nucleotide sequence, or partial sequence conjugation, modification, or substitution may all be included within the scope of the present invention. The polynucleotide may be used in the form of an expression cassette operably linked to a known promoter sequence, or a vector containing the polynucleotide, and the polynucleotide, expression cassette, or vector may be appropriately produced by a method known to those skilled in the art. The type of promoter and vector is not particularly limited, and may be appropriately selected by those skilled in the art depending on the purpose. The polynucleotide, expression cassette, or vector may be transformed into a host cell to produce a transformant for use, and the transformation method may also be a method known to those skilled in the art without any restrictions. The transformant is a subject in which the ADP-ribose binding peptide of the present invention is to be expressed, and may be a microorganism, a plant or an animal, excluding humans, but is not limited thereto.

[0041] Those skilled in the art can prepare and use a polynucleotide encoding the ADP-ribose binding peptide, a vector containing the polynucleotide, or a transformant containing the vector in order to apply / produce the ADP-ribose binding peptide for various purposes. For example, the polynucleotide or the vector can be used directly for cancer treatment, and a transformant expressing the ADP-ribose binding peptide can be used to produce the peptide or for treatment, but is not limited thereto.

[0042] Yet another embodiment of the present invention is a pharmaceutical composition for preventing or treating cancer, comprising the ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0043] Yet another aspect of the present invention is a use of the peptide or a pharma- ceutical acceptable salt thereof for the prevention or treatment of cancer, and a method for the prevention or treatment of cancer, comprising the step of administering the peptide or a pharma-ceutical acceptable salt thereof to an individual in need thereof.

[0044] As described above, the ADP-ribose binding peptide of the present invention has excellent effects in the prevention and / or treatment of cancer.

[0045] In the present invention, the term "cancer" refers to a disease associated with the regulation of cell death, which occurs when the normal balance of cell death is lost and cells begin to proliferate excessively. In the present invention, the cancer includes both malignant and benign tumors, and may be, for example, brain cancer, head and neck cancer, lung cancer, breast cancer, thymoma, esophageal cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovarian cancer, cervical cancer, endometrial cancer, colon cancer, lymphoma, acute leukemia, chronic leukemia, multiple myeloma, sarcoma, malignant melanoma, or skin cancer, but the types of cancer in the present invention are not limited by the above examples. The composition for preventing or treating cancer of the present invention has a therapeutic effect on all cancers in which cell death can occur due to the accumulation of intracellular ADP-ribose.

[0046] By way of example, the cancer may be a solid cancer such as, but not limited to, brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, kidney cancer, stomach cancer or ovarian cancer.

[0047] In the present invention, the term "treatment" refers to intervention to change the natural process of an individual or cell with a disease, which may be performed during or to prevent the progression of a pathological condition. The intended therapeutic effects include preventing the onset or recurrence of a disease, alleviating symptoms, reducing all direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, alleviating or temporarily alleviating a disease state, and improving the prognosis. In particular, in the present invention, the term "treatment" refers to any action that improves the course of cancer by administering a composition containing an ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof as an active ingredient. In addition, the term "prevention" refers to any action that inhibits or delays the onset of cancer by administering the composition.

[0048] The weight percentage of the ADP-ribose binding peptide or a pharma- ceutical acceptable salt thereof contained in the pharmaceutical composition is not particularly limited, but may be 0.0001 to 90% by weight, specifically 0.001 to 50% by weight, and more specifically 0.01 to 20% by weight, based on the total weight of the final composition.

[0049] The pharmaceutical composition may further include a suitable carrier, excipient, or diluent that is commonly used in the manufacture of medicines. Specifically, the pharmaceutical composition of the present invention may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and oral patches, topical preparations, topical patches, suppositories, and sterile injections by a conventional method.

[0050] When the pharmaceutical composition is used for oral administration, it can be prepared in a sustained release formulation through appropriate encapsulation, enteric coating, compounding with a polymer, or the like.

[0051] In one embodiment, the sustained release formulation may be prepared as a long acting formulation.

[0052] In one embodiment, for long-acting formulations, the polymer and lipid can be mixed in the appropriate ratio.

[0053] The pharmaceutical compositions of the present invention can be administered to individuals who have developed or are at risk of developing cancer. In the present invention, the term "individual" refers to all animals, including humans.

[0054] The pharmaceutical composition of the present invention can be administered to a subject in a pharma- ceutical effective amount. In the present invention, the term "administration" refers to introducing the pharmaceutical composition of the present invention into a subject in a suitable manner, and the administration route can be administered through various routes, such as oral or parenteral, as long as it can reach the target tissue. Examples of administration routes include oral, intramuscular, intravenous, intraarterial, subcutaneous, peritoneal, pulmonary, and nasal, and may be, for example, subcutaneous or oral, but are not limited thereto.

[0055] In the present invention, the term "pharmaceutical effective amount" means an amount sufficient to prevent and / or treat cancer with a reasonable benefit / risk ratio applicable to medical use. Appropriate dosage and administration frequency can be selected by methods known in the art, and the amount and administration frequency of the pharmaceutical composition of the present invention actually administered can be appropriately determined depending on various factors such as the type of symptoms to be treated, administration route, sex, health condition, diet, individual age, weight, and severity of disease.

[0056] In the present invention, pharma- ceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, including, for example, salts of inorganic ions such as sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, and iron, and salts of inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid, as well as salts of organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotic acid, and acetylsalicylic acid, and salts of amino acids such as lysine, arginine, and guanidine. In addition, there are salts of organic ions such as tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, benzyltrimethylammonium, and benzethonium that can be used in pharmaceutical reactions, purification, and separation processes. However, the types of salts referred to in the present invention are not limited by these listed salts.

[0057] Since the ADP-ribose binding peptide of the present invention has excellent anti-cancer activity, it can be prepared not only in the form of a pharmaceutical composition but also in the form of a functional food composition.

[0058] When the composition of the present invention is prepared in the form of a food composition, the food composition may contain additional ingredients that are commonly used in food to improve the smell, taste, appearance, etc. For example, food additives may be added. The additives are selected according to the type of food and used in appropriate amounts.

[0059] The food composition may be prepared as a health functional food, which is the same term as food for special health use (FoSHU) and refers to a food with high medical and therapeutic effects that is processed to efficiently exhibit bioregulatory functions in addition to providing nutrition. The health functional food may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc., to obtain useful effects in treating cancer.

[0060] Yet another embodiment of the present invention is an adjuvant anti-cancer pharmaceutical composition for enhancing reactivity to a second anti-cancer drug, comprising the ADP-ribose binding peptide or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0061] Yet another aspect of the present invention is a pharmaceutical composition for preventing or treating cancer, comprising (i) the ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof, and (ii) a second anticancer agent as active ingredients.

[0062] The ADP-ribose binding peptide and its pharma- ceutically acceptable salts are as described above.

[0063] The ADP-ribose binding peptide of the present invention has an anti-cancer effect by itself, and also has a very excellent effect as an adjuvant anti-cancer pharmaceutical composition for the purpose of enhancing reactivity to a second anti-cancer drug. Therefore, the ADP-ribose binding peptide or a pharma- ceutical acceptable salt thereof can be used as a pharmaceutical composition for preventing or treating cancer by using a second anti-cancer drug as an active ingredient.

[0064] In the present invention, the term "second anticancer drug" refers to any drug having anticancer activity, except the ADP-ribose binding peptide of the present invention. In the present invention, the scope of the second anticancer drug is not particularly limited, and a person skilled in the art can select an appropriate type for use according to the type and progression of cancer, the purpose of curing, controlling, alleviating symptoms, etc. of cancer. The second anticancer drug may be, for example, a cytotoxic anticancer drug, a targeted anticancer drug, an immune anticancer drug, or a metabolic anticancer drug, but is not limited thereto.

[0065] In the present invention, a cytotoxic anticancer drug is a drug that exhibits an anticancer effect by attacking cancer cells that indiscriminately divide at a faster rate than normal cells, and has the same meaning as that commonly used in the technical field to which the present invention belongs. The cytotoxic anticancer drug includes alkylating agents, antimetabolites, and natural product anticancer agents.

[0066] The alkylating agent may include, but is not limited to, nitrogen mustards (e.g., cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, etc.), alkylsulfonates (e.g., busulfan, procarbazine, etc.), nitrosoureas (e.g., carmustine, lomustine, streptozocin, etc.), platinum-based alkylating agents (e.g., cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, etc.). The alkylating agent may induce the destruction of cancer cells by binding to DNA in cancer cells and damaging the DNA structure.

[0067] The antimetabolic agent may include, but is not limited to, pyrimidine derivatives (e.g., 5-fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine, etc.), folate derivatives (e.g., methotrexate, pemetrexed, etc.), and purine derivatives (e.g., mercaptopurine, etc.). The antimetabolic agent can induce cancer cell death by suppressing metabolism required for DNA replication and cell survival.

[0068] Examples of the natural product anticancer drugs include, but are not limited to, topoisomerase inhibitors (e.g., camptothecin, epipodophyllotoxin, taxane series drugs (docetaxel, paclitaxel)), antibiotics (e.g., dactinomycin, doxorubicin, daunorubicin, mitomycin, phleomycin, idarubicin, mitoxantrone HCl, etc.).

[0069] In the present invention, the targeted anticancer drug is an anticancer drug that induces the death of cancer cells by inhibiting a target protein (receptor or enzyme) involved in the growth of cancer, and has the same meaning as that commonly used in the technical field to which the present invention belongs. The cytotoxic anticancer drug includes a small molecule compound that inhibits a target protein (such as tyrosine kinase) and a monoclonal antibody.

[0070] As an example, the targeted anti-cancer drug may be a receptor tyrosine kinase inhibitor that targets one or more targets selected from the group consisting of VEGF-A and EGFR.

[0071] In one embodiment, the targeted anticancer drug that can be administered in combination with ADP-ribose binding peptide is a VEGF-A inhibitor.In the present invention, the VEGF-A inhibitor can include monoclonal antibodies such as bevacizumab, ranibizumab, aflibercept, and ramucirumab, and small molecule compounds such as sunitinib, pazopanib, sorafenib, and axitinib, but is not limited thereto.

[0072] In one embodiment, the targeted anticancer drug that can be administered in combination with ADP-ribose binding peptide is an EGFR inhibitor.In the present invention, the EGFR inhibitor can include, but is not limited to, small molecule compounds such as osimertinib, gefitinib, erlotinib, afatinib, brigatinib, icotinib, vandetanib, as well as monoclonal antibodies such as cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.

[0073] In addition, the targeted anticancer agent of the present invention also includes HER2 targeted anticancer agents such as lapatinib, neratinib, and afatinib; Bcr-Abl targeted anticancer agents such as imatinib, dasatinib, and nilotinib; Src targeted anticancer agents such as bosutinib; JAK targeted anticancer agents such as lestaurtinib, ruxolitinib, and pacritinib; and MAP2 targeted anticancer agents such as cobimethinib, selumetinib, trametinib, and binimetinib. Kinase-targeted anticancer drugs include MEL4-ALK-targeted anticancer drugs such as ceritibin and crizotinib, and are not particularly limited in type.

[0074] The second anti-cancer agent of the present invention may also be a combination of one or more cytotoxic and / or targeted anti-cancer agents, which may be administered simultaneously or at different times.

[0075] In the present invention, the immune anticancer drug refers to a drug that activates the immune system of the human body to fight against cancer cells. In the present invention, the immune anticancer drug includes immune checkpoint inhibitors, immune cell therapy agents, anticancer vaccines, and antibody-drug conjugates, and an appropriate type can be selected for the complete cure, regulation, and symptom relief of cancer depending on the type and progression of cancer.

[0076] In one embodiment, the immune anti-cancer agent may be an immune checkpoint inhibitor, and may be one or more selected from the group consisting of PD-1 antibody, PD-L1 antibody, CTLA-4 antibody, CD28 antibody, KIR antibody, TCR antibody, LAG-3 antibody, TIM-3 antibody, TIGIT antibody, A2aR antibody, ICOS antibody, OX40 antibody, 4-1BB antibody, and GITR antibody. For example, the immune checkpoint inhibitor may be, but is not limited to, a PD-1 antibody such as nivolumab, pembrolizumab, cemiplimab, pidilizumab, or toripalimab; a PD-L1 antibody such as atezolizumab, avelumab, or durvalumab; or a CTLA-4 antibody such as ipilimumab or tremelimumab.

[0077] In one embodiment, the immune anti-cancer agent may be an immune cell therapy, which may be, but is not limited to, a CAR-T therapy such as tisagenlecleucel, axicabtagene ciloleucel, or a CAR-NK therapy.

[0078] In the present invention, the metabolic anticancer drug refers to a drug that is involved in the growth and survival of cancer cells, such as by supplying nutrients to cancer cells, or is involved in various essential metabolic actions to kill cancer cells. The metabolic anticancer drug may be, for example, IM-156, 3-bromopyruvic acid (3BP), NYH817100, WZB117, GNE-140, AZ93, AZD3965, CPI-613, MKT-077, CB-839, CB-1158, CPI-444, TVB-2640, NDI-010976, TCD-717, ADI-PEG20, epacadostat, indoximod, PX478, CPI-0610, RTA402, APO866, GMX1778, AG-221, or AG-120, but is not limited thereto.

[0079] The ADP-ribose binding peptide of the present invention can be used as an anticancer adjuvant by disrupting the balance of ADP-ribose in cancer cells and enhancing the reactivity to a second anticancer drug, and is not particularly limited by the type of second anticancer drug used or the type of cancer. For example, the cancer may be a solid cancer such as brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, kidney cancer, stomach cancer, or ovarian cancer, but is not limited thereto.

[0080] The ADP-ribose binding peptide of the present invention may be administered in a form that exists independently in combination with a second anticancer drug, or may be administered in a form that forms a physical / chemical bond with the second anticancer drug by any known method according to the purpose. For example, the ADP-ribose binding peptide may be used in a state that is directly bound to the second anticancer drug, or in a state that is linked to the second anticancer drug via a known linker, and there is no particular limitation on the application method as long as the ADP-ribose binding peptide of the present invention acts together with the second anticancer drug to show a synergistic anticancer effect.

[0081] In a specific embodiment of the present invention, when the ADP-ribose binding peptide of the present invention was treated with low concentrations of bevacizumab, osimertinib, gemcitabine, and docetaxel in different cancer types, it was confirmed that the reactivity to the anticancer drug was enhanced in all cancer cells (FIGS. 13 and 14). Therefore, the ADP-ribose binding peptide of the present invention can enhance the response of a second anticancer drug and can be very usefully used as an anticancer adjunct, and since it has excellent anticancer activity even when the second anticancer drug is treated at a low concentration, it can minimize side effects that may occur due to the second anticancer drug.

[0082] Yet another embodiment of the present invention is an adjuvant pharmaceutical composition for anti-cancer therapy, which comprises the ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof as an active ingredient, and enhances responsiveness to anti-cancer radiation therapy.

[0083] The ADP-ribose binding peptide and its pharma- ceutically acceptable salts are as described above.

[0084] In the present invention, the term "anti-cancer radiation therapy" refers to a therapeutic procedure in which cancer cells or tumor tissues are irradiated with radiation for the purpose of killing the cancer cells. Generally, it is a standard treatment for controlling inoperable or inoperable tumors or tumor metastasis, and is based on the principle that radiation delivered to the target site causes the death of reproductive cells. In the present invention, the anti-cancer radiation therapy may be, but is not limited to, ionizing radiation therapy, electromagnetic radiation, brachytherapy, or external beam radiation therapy.

[0085] The composition comprising the ADP-ribose binding peptide or its pharma- ceutically acceptable salt according to the present invention shows a synergistic anticancer effect when used in combination with radiotherapy, and can be usefully used as an anticancer adjuvant for radiotherapy or a radiosensitizer for improving radiosensitivity, and is not particularly limited in the type of cancer to which it can be applied. For example, the cancer may be solid cancer such as brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, kidney cancer, stomach cancer, and ovarian cancer, but is not limited thereto.

[0086] In one embodiment, the solid tumor may be resistant to radiotherapy. Since the anti-cancer effect of radiotherapy is indicated by the formation of DNA breaks, the resistance to radiotherapy is generally determined by the mechanism capable of repairing DNA damage induced by radiotherapy. There have been many attempts to inhibit DNA repair mechanisms as a way to synergize the anti-cancer efficacy of radiotherapy, and blocking the repair of broken DNA strands may increase the sensitivity of radiotherapy. The two main forms of DNA damage are SSBs (single strand breaks) and DSBs (double strand breaks). Thus, they can be described in the category of two repair pathways targeting SSBs and DSBs. Base excision repair (BER) is one of the various pathways involved in the repair of selected types of DNA SSBs.

[0087] PARP1 plays an important role in the BER of DNA SSBs through a process known as ADP-ribosylation. In the nucleus, PARP1 senses SSB DNA damage and recruits DNA repair complexes to SSB sites through ADP-ribosylation for repair. Since the overaccumulation of poly-ADP-ribose synthesized through ADP-ribosylation by PARP-1 activity ultimately leads to cell death, cancer cells activate the degradation of poly-ADP-ribose through proteasomes such as PARG and ARH3 to prevent this phenomenon and activate survival signaling activity. The present inventors have found that the accumulation of ADP-ribose and ADP-ribose polymers in cancer cells can act as a mediator that can disrupt such biochemical survival mechanisms of cancer cells and can be used as an important anticancer adjuvant to overcome radiation therapy resistance.

[0088] In a specific embodiment of the present invention, it was confirmed that when the ADP-ribose binding peptide of the present invention was co-treated with low-dose radiation irradiation in different cancer types, the response to radiation therapy was enhanced in all cancer types (Figures 15 and 16). Therefore, the ADP-ribose binding peptide of the present invention can enhance the response to radiation therapy and can be very usefully used as an anti-cancer adjunct, and since it has excellent anti-cancer activity even when irradiated with a tolerable dose of radiation, it can minimize side effects that may occur due to radiation.

[0089] The embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Moreover, the embodiments of the present invention are provided to more completely explain the present invention to those having average knowledge in the art. Furthermore, throughout the specification, "including" a certain component does not exclude other components, and means that other components can be further included, unless otherwise specified to the contrary.

[0090] [Mode for carrying out the invention] The present invention will be described in more detail with reference to the following examples, which are merely for illustrative purposes and are not intended to limit the scope of the present invention.

[0091] Example 1-14. Preparation of ADP (adenosine diphosphate)-ribose-linked peptide The ADP-ribose binding peptides of Examples 1 to 14 were synthesized from the WWE domains present in various proteins and used in the experiments. Specific information on the peptides used is shown in Table 1 below.

[0092] [Table 1]

[0093] In addition, a cell-penetrating peptide was bound to the N-terminus of each of the peptides of Examples 1 to 14 to prepare the peptides of Examples 15 to 28. The peptide sequences of Examples 15 to 28 are shown in Table 2.

[0094] [Table 2]

[0095] Experimental example 1: Confirmation of changes in ADP (adenosine diphosphate)-ribose levels in cancer cells The peptides of Examples 1 to 28 of the present invention were designed to be capable of inhibiting the enzyme activity of decomposing poly ADP-ribose. In Experimental Example 1, it was confirmed through cell experiments whether each peptide inhibits the decomposition of poly ADP-ribose and accumulates in cancer cells.

[0096] 1-1.Changes in ADP-ribose levels in U-87MG cells 5×10 5U-87MG cells were cultured for 24 hours at 37℃, 5% CO2 in EMEM (Eagle's Minimum Essential Medium) containing 10% FBS, 100 units / ml penicillin and 100μg / ml streptomycin, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32μM of the peptide of Example 1 (SEQ ID NO: 1) or Example 8 (SEQ ID NO: 8). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0097] The upper left of FIG. 1 and the lower right of FIG. 2 show the fold change in the amount of ADP-ribose increased in U-87MG cells by the treatment with the peptides of Examples 1 and 8 compared to the control group. It is shown that the amount of ADP-ribose significantly increased in a concentration-dependent manner for both treated peptides compared to the untreated group ( ** p<0.001).

[0098] 1-2. Changes in ADP-ribose levels in H1975 cells 5×10 5 H1975 cells were cultured for 24 hours at 37℃, 5% CO2 in RPMI-1640 medium containing 10% FBS, 100 units / ml penicillin, and 100μg / ml streptomycin, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32μM of the peptide of Example 2 (SEQ ID NO:2). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0099] The top right of Figure 1 and the top left of Figure 3 show the fold change in the amount of ADP-ribose increased in H1975 cells by treatment with the peptides of Example 2 or Example 9 compared to the control group, and show that the amount of ADP-ribose significantly increased in a peptide concentration-dependent manner compared to the untreated group (**p<0.001).

[0100] 1-3.Changes in ADP-ribose levels in Aspc-1 cells 5×10 5 Aspc-1 cells were cultured in RPMI-1640 medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin at 37°C and 5% CO2 for 24 hours, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32 μM of the peptide of Example 3 (SEQ ID NO: 3). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0101] The lower left of FIG. 1 and the upper right of FIG. 3 show the fold change in the amount of ADP-ribose increased in Aspc-1 cells by treatment with the peptide of Example 3 or Example 10 compared to the control group, and show that the amount of ADP-ribose significantly increased in a peptide concentration-dependent manner compared to the untreated group ( ** p<0.001).

[0102] 1-4.Changes in ADP-ribose levels in Hep G2 cells 5×10 5 Hep G2 cells were divided into groups without the peptide of the example and groups with the peptide of the example 4 (SEQ ID NO: 4) of 0.2, 1, 2, 4, 8, 16, and 32 μM in EMEM medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin at 37°C and 5% CO2, and cultured for 24 hours. The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0103] The lower right of FIG. 1 and the lower left of FIG. 3 show the fold change in the amount of ADP-ribose increased in Hep G2 cells by the treatment with the peptide of Example 4 or Example 11 compared to the control group, and show that the amount of ADP-ribose significantly increased in a peptide concentration-dependent manner compared to the untreated group (** p<0.001).

[0104] 1-5.Changes in ADP-ribose levels in MDA-MB-231 cells 5×10 5 MDA-MB-231 cells were cultured in Leibovitz's L-15 medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin at 37°C and 5% CO2 for 24 hours, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32 μM of the peptide of Example 5 (SEQ ID NO: 5). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0105] The upper left of FIG. 2 and the lower right of FIG. 3 show the fold change in the amount of ADP-ribose increased in MDA-MB-231 cells by treatment with the peptide of Example 5 or Example 12 compared to the control group, and show that the amount of ADP-ribose is significantly increased in a peptide concentration-dependent manner compared to the untreated group ( ** p<0.001).

[0106] 1-6. Changes in ADP-ribose levels in HCT116 cells 5×10 5 HCT116 cells were cultured at 37℃, 5% CO2 in McCoy's 5A medium containing 10% FBS, 100 units / ml penicillin, and 100μg / ml streptomycin for 24 hours, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32μM of the peptide of Example 6 (SEQ ID NO:6). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0107] The upper right of FIG. 2 and the left side of FIG. 4 show the fold change in the amount of ADP-ribose increased by the peptide treatment of Example 6 or Example 13 in HCT116 cells compared to the control group, and show that the amount of ADP-ribose significantly increased in a peptide concentration-dependent manner compared to the untreated group ( ** p<0.001).

[0108] 1-7.Changes in ADP-ribose levels in Caki-1 cells 5×10 5 Caki-1 cells were cultured at 37℃, 5% CO2 in McCoy's 5A medium containing 10% FBS, 100 units / ml penicillin, and 100μg / ml streptomycin for 24 hours, divided into a group not treated with the example peptide and a group treated with 0.2, 1, 2, 4, 8, 16, and 32μM of the peptide of Example 7 (SEQ ID NO: 7). The culture medium of the cultured cells was removed, and treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect ADP-ribose.

[0109] The lower left of FIG. 2 and the right of FIG. 4 show the fold change in the amount of ADP-ribose increased in Caki-1 cells by the treatment with the peptide of Example 7 or Example 14 compared to the control group. It shows that the amount of ADP-ribose is significantly increased in a peptide concentration-dependent manner compared to the untreated group ( ** p<0.001).

[0110] Experimental Example 2: Change in cancer cell viability by treatment with the peptide of the present invention Cells maintain biochemical homeostasis and balance the production and degradation of ADP-ribose, and because cancer cells divide continuously and grow rapidly, if this balance is disrupted, their survival can be significantly affected compared to normal cells.

[0111] According to the results of the above-mentioned Experimental Example 1, when the peptides of the examples of the present invention are treated in cancer cells, the amount of intracellular ADP-ribose is significantly increased, which may lead to the homeostasis of the cancer cells being disturbed. Therefore, in Experimental Example 2, the survival rate of the cancer cells treated with the peptides of Examples 1 to 28 was measured.

[0112] 2-1. Change in viability of U-87MG cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3 U-87MG cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0113] The top left of Figure 5 and the top right of Figure 8 are representative micrographs of U-87MG cells treated with the peptides of Examples 1, 15, 8 and 22, respectively, and of untreated groups. In common, the U-87MG cells can be observed to grow rapidly in the group not treated with peptides, whereas the U-87MG cells can be observed to grow and die in the group treated with the peptides of the examples of the present invention. In particular, it was confirmed that the cancer cells were completely killed in the groups treated with the peptides of Examples 15 and 22, which have cell-penetrating peptides (CPPs) attached thereto.

[0114] 2-2. Changes in viability of H1975 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3H1975 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0115] The top right of Figure 5 and the top left of Figure 9 are representative micrographs of groups of H1975 cells treated with the peptides of Examples 2, 16, 9, and 23, respectively, and groups of untreated H1975 cells. In common, the group of untreated H1975 cells shows a rapid growth, whereas the group of treated H1975 cells shows a suppressed growth and death. In particular, it was confirmed that the cancer cells were completely killed in the groups of treated with the peptides of Examples 16 and 23 to which CPPs were attached.

[0116] 2-3. Changes in viability of Aspc-1 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3 Aspc-1 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. Then, after further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0117] The top left of Figure 6 and the top right of Figure 9 are representative micrographs of Aspc-1 cells treated with the peptides of Examples 3, 17, 10, and 24, respectively, and of untreated Aspc-1 cells. In general, in the group not treated with peptides, the Aspc-1 cells were observed to grow rapidly, whereas in the group treated with the peptides of the examples of the present invention, the Aspc-1 cells were observed to grow and die. In particular, it was confirmed that the cancer cells were completely killed in the groups treated with the peptides of Examples 17 and 24 to which the cell-penetrating peptide CPP was attached.

[0118] 2-4. Changes in viability of Hep G2 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3 Hep G2 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0119] The top right of Figure 6 and the top left of Figure 10 are representative micrographs of Hep G2 cells treated with the peptides of Examples 4, 18, 11, and 25, respectively, and of untreated groups. In general, the Hep G2 cells in the untreated groups were observed to grow rapidly, whereas the Hep G2 cells in the groups treated with the peptides of the examples of the present invention were observed to grow and die. In particular, it was confirmed that the cancer cells in the groups treated with the peptides of Examples 18 and 25, to which the cell-penetrating peptide CPP was attached, were completely killed.

[0120] 2-5. Changes in viability of MDA-MB-231 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3MDA-MB-231 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. Then, after further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0121] The top left of Figure 7 and the top right of Figure 10 are representative micrographs of MDA-MB-231 cells treated with the peptides of Examples 5, 19, 12, and 26, respectively, and of untreated groups. In general, in the group not treated with peptides, the morphology of MDA-MB-231 cells rapidly growing can be observed, whereas in the group treated with the peptides of the examples of the present invention, the morphology of MDA-MB-231 cells suppressed in growth and dying can be observed. In particular, it was confirmed that cancer cells were completely killed in the groups treated with the peptides of Examples 19 and 26 to which CPP was attached.

[0122] 2-6. Changes in viability of HCT116 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3 HCT116 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0123] The top right of Figure 7 and the top left of Figure 11 are representative micrographs of groups of HCT116 cells treated with the peptides of Examples 6, 20, 13, and 27, respectively, and groups of cells not treated with the peptides. In general, the group not treated with the peptides shows rapid growth of HCT116 cells, whereas the group treated with the peptides of the examples of the present invention shows suppressed growth and death of HCT116 cells. In particular, it was confirmed that cancer cells were completely killed in the groups treated with the peptides of Examples 20 and 27 to which the cell-penetrating peptide CPP was attached.

[0124] 2-7. Changes in viability of Caki-1 cells treated with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3 Caki-1 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 1 to 28 at a concentration of 16 μM. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0125] The top left of Figure 8 and the top right of Figure 11 are representative micrographs of Caki-1 cells treated with and without the peptides of Examples 7, 21, 14, and 28, respectively. In common, the Caki-1 cells can be observed to grow rapidly in the group not treated with peptides, whereas the Caki-1 cells can be observed to grow and die in the group treated with the peptides of the examples of the present invention. In particular, it was confirmed that the cancer cells were completely killed in the groups treated with the peptides of Examples 21 and 28 to which CPPs were attached.

[0126] 2-8. Changes in viability of SNU-1 and OVCAR-3 cells following treatment with ADP-ribose-binding peptides 3 x 10 in a 96-well plate 3SNU-1 cells or OVCAR-3 cells were cultured at 37°C and 5% CO2 for 24 hours, and then either untreated or treated with the peptides of Examples 15 to 28 at a concentration of 16 μM. Then, after further culture at 37°C and 5% CO2 for 96 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0127] As a result, it was confirmed that the groups treated with each of the peptides of Examples 15 to 28 almost completely killed the cancer cells in both SNU-1 cells and OVCAR-3 cells (FIG. 12).

[0128] Experimental Example 3: Changes in cancer cell viability by combined treatment with the peptide of the present invention and low-concentration anticancer drugs Since the anti-cancer effect represented by the reduction in cancer cell survival caused by existing anti-cancer drugs can be synergized by ADP-ribose signal, it was expected that when existing anti-cancer drugs are treated to induce the accumulation of ADP-ribose, a synergistic anti-cancer effect would be exhibited even if the cancer cells were treated with the existing anti-cancer drugs at a concentration lower than the required concentration. As confirmed in the above Experimental Example 1, the example peptide of the present invention significantly increases the amount of ADP-ribose in cancer cells, so in Experimental Example 3, it was attempted to confirm whether a synergistic anti-cancer effect would be exhibited when the example peptide was treated in combination with a low concentration of an anti-cancer drug.

[0129] 3-1. Change in viability of U-87MG cells after combined treatment with the example peptide and low-concentration bevacizumab 3 x 10 in a 96-well plate 3U-87MG cells were cultured for 24 hours at 37°C and 5% CO2, and then treated with 18 mM bevacizumab alone or in combination with the peptides of Examples 1 to 14 at 0.2, 1 or 8 μM concentrations. After further culture for 24 hours at 37°C and 5% CO2, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0130] As a result, when U-87MG cells were treated with bevacizumab alone, about 49% of all cancer cells survived, but in all cases where the cells were treated in combination with the example peptide, it was confirmed that even at low concentrations of bevacizumab, the survival rate of the cancer cells was significantly reduced ( * p<0.05, ** p<0.001, *** p<0.001; left side of Figure 13 ).

[0131] 3-2. Change in viability of H1975 cells after combined treatment with the example peptide and low-concentration osimertinib 3 x 10 in a 96-well plate 3 H1975 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 1 nM osimertinib alone or in combination with the peptides of Examples 1 to 14 at 0.2, 1 or 8 μM concentrations. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0132] As a result, when H1975 cells were treated with 1 nM osimertinib alone, approximately 49% of all cancer cells survived, but in all cases where the cells were treated in combination with the example peptide, it was confirmed that even at low concentrations of osimertinib, the survival rate of the cancer cells was significantly reduced ( * p<0.05, ** p<0.001, ***p<0.001; right side of Figure 13 ).

[0133] 3-3. Change in viability of Aspc-1 cells by combined treatment of the example peptide and low-concentration gemcitabine 3 x 10 in a 96-well plate 3 Aspc-1 cells were cultured for 24 hours at 37°C and 5% CO2, and then treated with 1 μM gemcitabine alone or in combination with the peptides of Examples 15 to 28 at 0.2, 1, or 8 μM concentrations. After further culture for 24 hours at 37°C and 5% CO2, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0134] As a result, when ASPC-1 cells were treated with gemcitabine alone, approximately 50% of all cancer cells survived, but in all cases where gemcitabine was co-treated with the example peptide, it was confirmed that even at low concentrations of gemcitabine, the survival rate of the cancer cells was significantly reduced ( * p<0.05, ** p<0.001, *** p<0.001; left side of Figure 14 ).

[0135] 3-4. Change in viability of MDA-MB-231 cells after combined treatment with the example peptide and low-concentration docetaxel 3 x 10 in a 96-well plate 3 MDA-MB-231 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 50μM docetaxel alone or in combination with the peptides of Examples 15 to 28 at 0.2, 1 or 8μM concentrations. After further culture at 37°C and 5% CO2 for 24 hours, 10μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200μl of dimethylsulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0136] As a result, when MDA-MB-231 cells were treated with docetaxel alone, approximately 52% of all cancer cells survived, but in all cases where the cells were treated in combination with the example peptide, it was confirmed that even at low concentrations of docetaxel, the survival rate of the cancer cells was significantly reduced ( * p<0.05, ** p<0.001, *** p<0.001; right side of Figure 14 ).

[0137] Experimental Example 4: Changes in cancer cell viability by combined treatment with the peptide of the present invention and radiation Radiation therapy is expected to have an anti-cancer effect through its killing action by damaging genetic material, but cancer cells overcome this by continuously repairing DNA strands through a process known as ADP-ribosylation. However, it was expected that if ADP-ribose, which is only temporarily increased by the repair action caused by radiation exposure, is continuously accumulated, a synergistic anti-cancer effect would be obtained even if a tolerable dose of radiation was applied. As confirmed in the above Experimental Example 1, the example peptide of the present invention significantly increases the amount of ADP-ribose in cancer cells, so in Experimental Example 4, it was attempted to confirm whether a synergistic anti-cancer effect would be obtained when the example peptide was used in combination with a tolerable dose of radiation exposure.

[0138] 4-1. Change in survival rate of H1975 cells after combined treatment with the example peptide and a resistant dose of radiation 3 x 10 in a 96-well plate 3 H1975 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 2Gy dose of radiation alone or with 1.6 or 3.2μM of peptides of SEQ ID NO:1-14. After further culture at 37°C and 5% CO2 for 24 hours, 10μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200μl of dimethylsulfoxide was added to each well, and the absorbance was measured to confirm the survival rate of the cells.

[0139] As a result, when H1975 cells were treated with 2 Gy of radiation alone, about 76% of the cancer cells showed resistance to survival compared to the untreated group. However, in all cases where the cells were treated in combination with the example peptide, it was confirmed that the survival rate of the cancer cells was significantly reduced even at the radiation exposure dose that was resistant to radiation ( ** p<0.001, *** p<0.001; left side of Figure 15 ).

[0140] 4-2. Change in survival rate of Aspc-1 cells by combined treatment with the example peptide and a resistant dose of radiation 3 x 10 in a 96-well plate 3 Aspc-1 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 2Gy dose of radiation alone or with 1.6 or 3.2μM of peptides of SEQ ID NO:1-14. After further culture at 37°C and 5% CO2 for 24 hours, 10μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200μl of dimethylsulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0141] As a result, when Aspc-1 cells were treated with 2 Gy of radiation alone, about 86% of the cancer cells showed resistance to survival compared to the untreated group. However, in all cases where the cells were treated in combination with the example peptide, it was confirmed that the survival rate of the cancer cells was significantly reduced even at the radiation dose that was resistant to radiation ( ** p<0.001, *** p<0.001; right side of Figure 15 ).

[0142] 4-3. Change in survival rate of MDA-MB-231 cells after combined treatment with the example peptide and a resistant dose of radiation 3 x 10 in a 96-well plate 3MDA-MB-231 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 2Gy dose of radiation alone or with 1.6 or 3.2μM peptides of SEQ ID NO:15-28. After further culture at 37°C and 5% CO2 for 24 hours, 10μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the viability of the cells.

[0143] As a result, when MDA-MB-231 cells were treated with 2 Gy of radiation alone, about 86% of the cancer cells showed resistance to survival compared to the untreated group. However, in all cases where the cells were treated in combination with the example peptide, it was confirmed that the survival rate of the cancer cells was significantly reduced even at the radiation exposure dose that was resistant to radiation ( ** p<0.001, *** p<0.001; left side of Figure 16 ).

[0144] 4-4. Change in survival rate of Caki-1 cells by combined treatment with the example peptide and a resistant dose of radiation 3 x 10 in a 96-well plate 3 Caki-1 cells were cultured at 37°C and 5% CO2 for 24 hours, and then treated with 2 Gy radiation alone or in combination with 1.6 or 3.2 μM peptides of SEQ ID NOs: 15 to 28. After further culture at 37°C and 5% CO2 for 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and reacted for 1 hour. After removing the reacted reagent, 200 μl of dimethyl sulfoxide was added to each well, and the absorbance was measured to confirm the cell viability.

[0145] As a result, when Caki-1 cells were treated with 2 Gy of radiation alone, about 96% of the cancer cells showed resistance to survival compared to the untreated group. However, in all cases where the cells were treated in combination with the example peptide, it was confirmed that the survival rate of the cancer cells was significantly reduced even at the radiation exposure dose that was resistant to radiation ( ** p<0.001,*** p<0.001; right side of Figure 16 ).

[0146] Experimental Example 5: Comparison and verification of anti-cancer efficacy according to administration route of example peptide using animal model 5-1. Change in tumor volume in animal models where the example peptide was injected subcutaneously Five-week-old BALB / c nude mice were inoculated with ASPC-1 cells (1 × 10 7 The mice were inoculated into the back of the flank and divided into 15 groups, including a non-treated control group and one of the peptides of Examples 15 to 28, which were each injected subcutaneously. 3 When the tumors grew to 100 mm Hg, each of the example peptides was subcutaneously injected at a dose of 20 mg / kg three times a week. The tumor size was measured using a digital camera, and the results of changes in tumor volume were compared between groups.

[0147] As a result, the final volume of the control group tumor after the final dose was approximately 3136 mm 3 However, it was confirmed that the tumor growth was significantly suppressed in all groups in which the peptides of Examples 15 to 28 were subcutaneously injected ( ** p<0.001; Figure 17).

[0148] FIG. 18 shows representative tumor photographs taken after autopsy in all groups. It was observed that the growth of tumor tissue was significantly suppressed in all groups that received subcutaneous injections of the example peptide of the present invention, compared to the control group.

[0149] 5-2. Change in tumor volume in animal models injected with the example peptide via the oral route Five-week-old BALB / c nude mice were inoculated with ASPC-1 cells (1 × 10 7 Mice were inoculated into the back of the flank and divided into 15 groups, including a non-treated control group and one of the peptides of Examples 1 to 14 administered orally. 3 When the tumors grew to 100 mm, each of the example peptides was orally administered at a dose of 20 mg / kg 5 times a week. The tumor size was measured using a digital camera, and the results of changes in tumor volume were compared between groups.

[0150] As a result, the final volume of the control group tumor after the final dose was approximately 3517 mm 3 However, it was confirmed that the tumor growth was significantly suppressed in all groups in which the peptides of Examples 1 to 14 were orally administered. ** p<0.001; Figure 19).

[0151] FIG. 20 shows representative tumor photographs taken after autopsy in all groups. It was observed that the growth of tumor tissue was significantly suppressed in all groups that received the example peptide of the present invention orally, compared to the control group.

[0152] Experimental Example 6: Confirmation of cytotoxicity of the example peptide in normal cells Next, we further confirmed whether the peptide of the present invention exhibits cytotoxicity in normal cells. For the test, human colon fibroblasts (CCD-18Co) and human dermal papilla cells (HDPC) were used as normal cells, and the peptide of SEQ ID NO: 7 was used as an example peptide of the present invention.

[0153] First, 5 × 10 3 After inoculation of each normal cell, it was cultured in DMEM medium at 37℃ and 5% CO2 for 24 hours. Each well was divided into a peptide-untreated group and a peptide-treated group of SEQ ID NO:7 (25, 50 and 100μM, respectively) to carry out the experiment.

[0154] As a result of the experiment, no significant difference was found between the peptide-treated groups (24 hours, 48 ​​hours, or 72 hours after treatment) and the untreated control group (Figures 21 and 22). Therefore, it was confirmed that the peptide of the present invention has a very excellent effect for anti-cancer use because it shows strong anti-cancer activity in cancer cells while showing no cytotoxicity in normal cells.

[0155] From the above description, a person skilled in the art to which the present invention pertains can understand that the present invention can be embodied in other specific forms without changing the technical idea or essential features of the present invention. In this regard, it should be understood that the above-described embodiments are illustrative in all respects and are not limiting. The scope of the present invention should be interpreted as including all modifications and variations derived from the meaning and scope of the claims below rather than the above detailed description, and the equivalent concepts thereof.

Claims

1. An isolated ADP (adenosine diphosphate)-ribose binding peptide, comprising any one of the amino acid sequences selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:

3.

2. The ADP-ribose binding peptide of claim 1, further comprising a cell-penetrating peptide at the N-terminus, C-terminus or both termini.

3. The ADP-ribose binding peptide according to claim 2, wherein the cell-penetrating peptide is at least one selected from the group consisting of TAT, maurocalcine, penetratin, poly-arginine-derived peptide, antennapedia, transportan, VP22, Hph-1, poly-arginine, R11 (R9), Pep-1, HP4, LAH4, Vetofusing-1, signal sequence-based peptides, and amphipathic peptides.

4. The ADP-ribose binding peptide according to claim 2, wherein the peptide comprises any one of the amino acid sequences selected from the group consisting of SEQ ID NOs: 15 to 17.

5. A polynucleotide encoding the ADP-ribose binding peptide according to any one of claims 1 to 4.

6. A vector comprising the polynucleotide of claim 5.

7. A transformant comprising the polynucleotide of claim 5.

8. A pharmaceutical composition for preventing or treating cancer, comprising the ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

9. The pharmaceutical composition for preventing or treating cancer according to claim 8, wherein the cancer is one or more solid cancers selected from the group consisting of brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, kidney cancer, gastric cancer and ovarian cancer.

10. The pharmaceutical composition for preventing or treating cancer according to claim 8 , wherein the composition is administered subcutaneously or orally.

11. 5. An anti-cancer adjuvant pharmaceutical composition for enhancing reactivity to a second anti-cancer drug, comprising the ADP-ribose binding peptide or a pharma- ceutical acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

12. The anti-cancer adjuvant pharmaceutical composition according to claim 11, wherein the anti-cancer drug is a cytotoxic anti-cancer drug, a targeted anti-cancer drug, or a combination thereof.

13. The anti-cancer adjuvant pharmaceutical composition according to claim 11, wherein the cancer targeted by the second anti-cancer drug is one or more solid cancers selected from the group consisting of brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, gastric cancer and ovarian cancer.

14. (i) an ADP-ribose binding peptide according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt thereof; and (ii) A pharmaceutical composition for preventing or treating cancer, comprising a second anticancer agent as an active ingredient.

15. 5. An adjuvant anti-cancer pharmaceutical composition for enhancing responsiveness to anti-cancer radiation therapy, comprising the ADP-ribose binding peptide or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.

16. The anti-cancer adjuvant pharmaceutical composition according to claim 15, wherein the cancer targeted by the radiation anti-cancer therapy is one or more solid cancers selected from the group consisting of brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, kidney cancer, gastric cancer and ovarian cancer.

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