ADP-ribose-binding peptides with anticancer activity and their applications

Abstract

To provide an ADP (adenosine diphosphate)-ribose-binding peptide having anticancer activity.SOLUTION: Provided are an ADP-ribose-binding peptide of a specific amino acid sequence and a denatured object thereof, and a pharmaceutical composition for preventing or treating cancer and a pharmaceutical composition for assisting anti-cancer activity which contain them as an active ingredient. The ADP-ribose-binding peptide breaks equilibrium of a cell to kill a cancer cell by accumulating ADP-ribose in a cancer cell, and has excellent anti-cancer effect that does not express toxicity in a normal cell, and in the case where the peptide is administered in combination with administration of other anticancer agent or anti-cancer radiotherapy, it enhances responsiveness to the anticancer agent and radiotherapy, and has extremely excellent effect as an anti-cancer adjuvant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ADP (adenosine diphosphate)-ribose-linked peptide having anticancer activity, and more specifically, to an ADP-ribose-linked peptide having a specific amino acid sequence and its variants, and to a pharmaceutical composition for the prevention or treatment of cancer, and a pharmaceutical composition for adjunct anticancer use, containing the same as an active ingredient. [Background technology]

[0002] PARylation (poly ADP-ribosylation) is a post-translational modification process in which poly(adenosine diphosphate-ribose) polymers are covalently attached to proteins by PAR polymerases. Through PARylation, high-molecular-weight ADP-ribose chains are generated, which can induce unique intracellular biochemical effects that do not exhibit the small molecular dimension of deformation such as acetylation or methylation, nor the morphological forms of ubiquitination or SUMOylation. The balance of PARylation plays a crucial role in DNA damage repair, transcriptional regulation, chromatin structure alteration, oxidation / reduction homeostasis, diverse intracellular signaling, non-membrane structure formation, host-pathogen interactions, and RNA metabolic regulation (Juan et al., Cancers, 2020, 12(3):739).

[0003] PARylation is involved in the development of systemic diseases, including cancer, viral infections, and neurological degeneration. In particular, since PARylation originates from the activation of PARP-1, the anticancer efficacy of targeting ovarian cancer, prostate cancer, breast cancer, and other cancers by suppressing PARP-1 activity 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 only recently become known, and activation of PARylation can induce cell death through three major pathways typically. (Rebecca Gupte et al., Genes Dev. 2017, 31(2):101).

[0005] NAD + Depletion can damage cell metabolism that occurs in a cell energy crisis (ATP depletion), particularly the oxidative phosphorylation process. PARylation activation induced by extensive DNA damage consumes NAD + and has been proposed to kill cells through the subsequent effects of this action.

[0006] Also, the PAR polymers released from the nucleus after DNA repair can bundle on the mitochondrial membrane in the cytoplasm to release cell death-inducing factors and activate a pathway that mobilizes cell death-inducing factors into the nucleus. When the cell death factors move to the nucleus, they mediate large-scale DNA fragmentation and induce cell death. Energy depletion and cell death-inducing factors by PARylation are known to be related to the signal transduction of PAR 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 significantly to the complexity of the death mechanism.

[0007] And although the exact biochemical mechanism has not been clarified, it has been reported that PARP-1 itself can be degraded through autoPARylation of PARP-1 to induce cell death. However, cancer can cleverly avoid this death effect by activating various proteolytic enzymes to degrade excess PAR polymers involved in various biochemical actions necessary for cancer survival.

[0008] Therefore, contrary to attempts for PARylation inhibition such as existing PARP-1 inhibitors, activating PARylation or suppressing the degradation of PAR polymers can also be a strategy for discovering effective anti-cancer therapies. In particular, PARylation activation or suppression of PAR polymer degradation can be regarded as very promising targets in cancer cell-specific regions that undergo metabolic processes in a different manner from normal cells.

Summary of the Invention

Problems to be Solved by the Invention

[0009] As a result of intensive efforts to develop a novel anti-cancer agent, the inventors of the present invention have found that a peptide having the novel amino acid sequence of the present invention can ultimately prevent the utilization of ADP-ribose or PAR polymers from the actions of various intracellular degrading enzymes and signaling proteins through binding to ADP-ribose, overactivate PARylation, and disrupt the degradation process of PAR polymerases. As a result of this disruption, it has been confirmed that cancer cell death can be induced, and an epoch-making anti-cancer efficacy can be achieved, thus completing the present invention.

Means for Solving the Problems

[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. [[ID=​​​​​​Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cancer, an adjunct anti-cancer pharmaceutical composition for enhancing responsiveness to a second anti-cancer agent, and an adjunct anti-cancer pharmaceutical composition for enhancing responsiveness to radiotherapy, comprising the peptide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] Another object of the present invention is to provide a use of the peptide or a pharmaceutically 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 pharmaceutically acceptable salt thereof to an individual in need. [Effects of the Invention]

[0015] The ADP-ribose-binding peptide of the present invention has an excellent anticancer effect that causes cancer cells to die by accumulating ADP-ribose in cancer cells, thereby disrupting the cellular balance, while not showing toxicity to normal cells. Furthermore, when administered in combination with other anticancer drugs or radiation therapy, it enhances the responsiveness to anticancer drugs and radiation therapy, thus exhibiting a very excellent effect as an anticancer adjuvant. [Brief explanation of the drawing]

[0016] [Figure 1] This chart shows the intracellular poly-ADP-ribose levels after treating different cancer cells with peptides SEQ ID NOs. 1-4 at different concentrations. [Figure 2] This chart shows the intracellular poly-ADP-ribose levels after treating different cancer cells with peptides SEQ ID NOs. 5-8 at varying concentrations. [Figure 3] This chart shows the intracellular poly-ADP-ribose levels after treating different cancer cells with peptides numbered 9-12 at varying concentrations. [Figure 4] This chart shows the intracellular poly-ADP-ribose levels after treating different cancer cells with peptides from SEQ ID NOs. 13 and 14 at different concentrations. [Figure 5]This shows the results of treating different cancer cells with the peptides SEQ ID NO: 1, SEQ ID NO: 15, SEQ ID NO: 2, and SEQ ID NO: 16, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 6] This shows the results of treating different cancer cells with the peptides SEQ ID NOs: 3, 17, 4, and 18, respectively, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 7] This shows the results of treating different cancer cells with the peptides from Sequence ID No. 5, Sequence ID No. 19, Sequence ID No. 6, and Sequence ID No. 20, respectively, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 8] This shows the results of treating different cancer cells with the peptides SEQ ID NOs. 7, 21, 8, and 22, respectively, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 9] This shows the results of treating different cancer cells with the peptides from Sequence ID No. 9, Sequence ID No. 23, Sequence ID No. 10, and Sequence ID No. 24, respectively, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 10] This shows the results of treating different cancer cells with the peptides SEQ ID NO: 11, SEQ ID NO: 25, SEQ ID NO: 12, and SEQ ID NO: 26, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 11] This shows the results of treating different cancer cells with the peptides SEQ ID NO: 13, SEQ ID NO: 27, SEQ ID NO: 14, and SEQ ID NO: 28, and then checking the cell viability. The upper figure shows a cell image, and the lower graph shows the cell viability. [Figure 12]This shows the results of examining the cell viability after treating different cancer cells with peptides numbered 15 to 28. [Figure 13] This chart shows the cell viability of different cancer cells after treatment with bevacizumab (left) or osimertinib (right), either alone or in combination with the peptides SEQ ID NOs: 1 to 14. [Figure 14] This chart shows the cell viability of different cancer cells after treatment with gemcitabine (left) or docetaxel (right) alone, or in combination with peptides SEQ ID NOs. 15 to 28. [Figure 15] This shows the cell viability of different cancer cells after irradiation with 2 Gy of radiation alone, or in combination with peptides SEQ ID NOs: 1 to 14. [Figure 16] This shows the cell viability of different cancer cells after irradiation with 2 Gy of radiation alone, or in combination with peptides SEQ ID NOs. 15 to 28. [Figure 17] This shows the change in tumor volume over time after subcutaneous administration of peptides SEQ ID NOs. 15 to 28 to an animal model of tumor transplantation. [Figure 18] These are photographs of tumor tissue observed after subcutaneous administration of peptides SEQ ID NOs. 15 to 28 from an animal model of tumor transplantation. [Figure 19] This shows the change in tumor volume over time after oral administration of peptides SEQ ID NOs: 1 to 14 to an animal model of tumor transplantation. [Figure 20] These are photographs of tumor tissue observed after oral administration of peptides SEQ ID NOs. 1 to 14 from an animal model of tumor transplantation. [Figure 21] This is a representative result of evaluating the toxicity of the peptide of Sequence ID No. 7 to normal cells (CCD-18Co). [Figure 22] This is a representative result of evaluating the toxicity of the peptide of Sequence ID No. 7 to normal cells (HDPC). [Figure 23] This shows the structure of the peptide of Sequence ID No. 7. [Modes for carrying out the invention]

[0017] This can be explained in more detail as follows: On the other hand, each description and embodiment disclosed in the present invention may also apply to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0018] One embodiment of the present invention for achieving the above objective is an ADP (adenosine diphosphate)-ribose-linked peptide having one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NOs: 14.

[0019] In the present invention, the term "ADP-ribose" is used as a concept encompassing both isolated ADP-ribose itself and ADP-ribose polymers (poly ADP-ribose), and "ADP-ribose-bound peptide" means all peptides that have the activity to bind to ADP-ribose or ADP-ribose polymers and inhibit their degradation. In the present invention, the peptides are not merely formed by peptide bonds between the amino acids that constitute them, but also include modified forms such as peptide analogs and derivatives that have partially modified forms in order to improve properties such as stability and efficacy from the perspective of protein pharmaceuticals.

[0020] The inventors focused on the fact that, unlike conventional PARP-1 inhibitors which have been reported to have numerous anticancer effects by suppressing PARylation (poly ADP-ribosylation), anticancer effects can also be expected through the activation of PARylation or the inhibition of PAR polymer degradation. In particular, since cancer cells divide at a faster rate than normal cells and are highly metabolically active, the inventors expected that by overactivating PARylation or inhibiting the degradation of PAR polymers, cancer cells could be specifically killed without any special effect on normal cells that do not experience PARylation overactivation.

[0021] The ADP (adenosine diphosphate)-ribose-binding peptides having any one amino acid sequence selected from the group consisting of Sequence IDs 1 to 14 (Table 1) of the present invention all originated from the WWE domain. The WWE domain is a globular domain conserved in many proteins, such as deltex, Trip12, and poly-ADP-ribose polymerase homologs, and is named after the most conserved residue within the domain (L. Aravind, TRENDS in Biochemical Sciences, 2001, 26(5):273). It is known that some proteins possessing the WWE domain have an ADP-ribose-binding motif within the domain. The WWE domain of intracellular enzymes has been reported to mainly bind to ADP-ribose and induce its degradation. That is, the binding of specific enzymes to PAR or ADPR via the WWE domain is thought to be largely for the purpose of cancer cell survival (PNAS August 23, 2011 108(34)14103-14108).

[0022] However, there have been no reports whatsoever of the following: when a peptide containing a portion of the WWE domain is produced and used to treat cells, as in the present invention, ADP-ribose degradation is suppressed, intracellular ADP-ribose accumulates, and as a result, it exhibits excellent anti-cancer effects.

[0023] In one specific embodiment of the present invention, fragments of the WWE domain present in various types of proteins were synthesized, and their anticancer activity was irradiated. As a result, it was confirmed that when various types of cancer cells were treated with the ADP-ribose-binding peptides of Examples 1 to 14 (SEQ ID NOs: 1 to 14), the level of ADP-ribose in the cancer cells increased significantly (Figures 1 to 4). Furthermore, it was confirmed through in vitro experiments (Figures 5 to 11) that the balance of intracellular ADP-ribose was disrupted by the treatment with the peptides, suppressing the growth of cancer cells and causing them to almost completely die. It was also confirmed from tumor transplantation animal models that when the ADP-ribose-binding peptides of Examples 1 to 14 were administered subcutaneously or orally, the growth of in vivo tumor tissue decreased sharply (Figures 19 and 20).

[0024] Furthermore, in another specific embodiment of the present invention, the peptide of Sequence ID No. 7 was typically used to treat normal cells, and its cytotoxicity to normal cells was evaluated. As a result, it was confirmed that no toxicity was observed in normal cells (Figures 21 and 22).

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

[0026] The aforementioned ADP-ribose-conjugated peptides include not only peptides having any one amino acid sequence from SEQ ID NOs: 1 to 14, but also sequences in which one or more amino acids are added, substituted, or bonded to these sequences, as long as they fall within the same range as the present invention.

[0027] For example, any peptide having at least 80%, 90%, 95%, 97%, or 99% homology to any one amino acid sequence among Sequence IDs 1 to 14 of the present invention, and exhibiting efficacy corresponding to any one amino acid sequence among Sequence IDs 1 to 14, namely ADP-ribose binding activity and anticancer activity, is included within the scope of the present invention, even if it has an amino acid sequence in which a portion of the amino acid sequences of Sequence IDs 1 to 14 has been added, substituted, or compounded.

[0028] Furthermore, if a peptide consisting of any one of the amino acid sequences from sequence numbers 1 to 14 has the corresponding activity, then meaningless sequence additions before or after the amino acid sequence, naturally occurring mutations, or silent mutations thereof may also be included within the scope of the present invention.

[0029] In this invention, the term "homology" means the degree to which a given amino acid sequence or nucleotide sequence matches, and can be expressed as a percentage. In this specification, homologous sequences having identical or similar activity to a given amino acid sequence or nucleotide sequence are expressed as "% homology". This can be confirmed, for example, by using standard software that calculates parameters such as score, identity, and similarity, specifically BLAST2.0, or by comparing sequences by Southern hybridization experiments under defined strict conditions, the defined appropriate hybridization conditions are within the scope of the art 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] Furthermore, the peptides of the present invention may be modified, such as by chemical derivatization of one or more amino acids constituting the peptide, in order to further improve desired properties. It will be obvious to those skilled in the art that any such modification, as long as it has equivalent anticancer activity to the peptides of the present invention, falls within the scope of the present invention. Such derivatization may include, but is not limited to, acetylation, hydroxylation, methylation, amidation, pegylation, and the addition of carbohydrate or lipid components, cofactors, etc.

[0031] In one specific embodiment of the present invention, the peptide may be used in a form fused with an additional cell-penetrating peptide to enhance cell permeability. That is, the ADP-ribose-conjugated peptide may further contain cell-penetrating peptides at its N-terminus, C-terminus, or both ends. In this case, a linker may further be included between the ADP-ribose-conjugated peptide and the cell-penetrating peptide, which can be appropriately carried out by those skilled in the art.

[0032] In the present invention, the term "cell-permeable peptide" refers to a peptide having properties that can promote the intracellular uptake / absorption of various substances such as nanoparticles, compounds, DNA, and proteins. Specifically, the cell-permeable 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. Any peptide that can promote the intracellular movement of the ADP-ribose-binding peptide of the present invention can be appropriately selected by those skilled in the art.

[0033] In one specific embodiment of the present invention, the cell-permeable peptide TAT was fused to the N-terminus of the ADP-ribose-conjugated peptides of SEQ ID NOs. 1 to 14 of the present invention, and its anticancer activity was evaluated (SEQ ID NOs. 15 to 24, Table 2). As a result, it was confirmed that it possessed even better anticancer activity than when the ADP-ribose-conjugated peptides were used alone (Figures 5 to 12, 17 and 18). Therefore, not only the ADP-ribose-conjugated peptides of SEQ ID NOs. 1 to 14 of the present invention, but also the forms in which the cell-permeable protein is fused to the peptides, can be very usefully used as compositions for the prevention or treatment of cancer.

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

[0035] Furthermore, the ADP-ribose-binding peptide of the present invention may be used in conjunction with reagents known in the art that can deliver proteins to cells or enhance the efficiency of protein delivery in order to increase cell permeability. Such reagents may include, for example, Chariot TM (Active motif, Cat.30025), Xflect TM (Takara, Cat.631324), Pierce TM (ThermoFisher Scientific, Cat.89850), ProteoJuice TM (Merck, Cat.71281), PULSin TMThe examples are not limited to those described above, but include all other non-commercial reagents, as well as commercially available reagents such as (Poylplus transfection), as long as they can deliver the ADP-ribose-binding peptide of the present invention to cells.

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

[0037] Another embodiment of the present invention is a vector containing the polynucleotide.

[0038] Another embodiment of the present invention is a transformant containing the polynucleotide.

[0039] The ADP-ribose-bound peptide is as described 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%, 90%, 95%, 97%, or 99% homology thereto, and if the polypeptide translated therefrom exhibits efficacy corresponding to the ADP-ribose-binding peptide of the present invention, the addition of meaningless sequences to the 5'- and / or 3'-terminuses of the nucleotide sequence, or the formation, modification, or substitution of parts of the sequence, are all within the scope of the present invention. The polynucleotide can be used in the form of an expression cassette operably linked to a known promoter sequence, or a vector containing the polynucleotide, and the production of the polynucleotide, expression cassette, or vector can be appropriately carried out by methods known to those skilled in the art. The type of promoter and vector is not particularly limited and can be appropriately selected by those skilled in the art depending on the purpose. Furthermore, the polynucleotide, expression cassette, or vector can be used to transform host cells to produce transformants, and the transformation method can also be any method known to those skilled in the art without limitation. The transformant is a subject organism intended to express the ADP-ribose-binding peptide of the present invention, and may be a microorganism, plant, or animal, excluding humans, but is not limited thereto.

[0041] Those skilled in the art can prepare and use polynucleotides encoding the ADP-ribose-conjugated peptide, vectors containing the same, or transformants containing the vector to apply / produce the ADP-ribose-conjugated peptide for a variety of purposes. For example, the polynucleotide or the vector can be used directly for therapeutic purposes against cancer, or the peptide can be produced or used for therapeutic purposes using transformants containing the same that express the ADP-ribose-conjugated peptide.

[0042] Another embodiment of the present invention is a pharmaceutical composition for the prevention or treatment of cancer, comprising the ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0043] Another embodiment of the present invention is a method for the prevention or treatment of cancer, comprising the use of the peptide or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer, and administering the peptide or a pharmaceutically acceptable salt thereof to an individual in need.

[0044] As stated above, the ADP-ribose-binding peptide of the present invention has excellent efficacy in preventing and / or treating 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 disrupted, leading to excessive cell proliferation. In the present invention, the term "cancer" includes all malignant and benign tumors, and may include, for example, brain cancer, head and neck cancer, lung cancer, breast cancer, thymoma, esophageal cancer, colorectal 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, colorectal 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 cancer prevention or treatment composition 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] For example, the aforementioned cancer may be, but is not limited to, solid tumors such as brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, stomach cancer, or ovarian cancer.

[0047] In this invention, the term “treatment” refers to an intervention to alter the natural processes of an individual or cell having a disease, which may be carried out during or to prevent the progression of a pathological condition. The desired therapeutic effects include preventing the onset or recurrence of the disease, alleviating symptoms, reducing all direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, mitigating or temporarily alleviating the disease state, improving recovery, or improving prognosis. In particular, in this invention, all actions that improve the course of cancer by administering a composition containing an ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof as an active ingredient. The term “prevention” also refers to all actions that suppress or delay the onset of cancer by administering the said composition.

[0048] The weight percentage of the ADP-ribose-bound peptide or its pharmaceutically acceptable salt contained in the pharmaceutical composition is not particularly limited, but may be 0.0001 to 90% by weight, more 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 compositions may further contain suitable carriers, excipients, or diluents commonly used in the manufacture of pharmaceuticals. Specifically, the pharmaceutical compositions of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms such as oral patches, topical preparations, topical patches, suppositories, and sterile injections, each by conventional methods.

[0050] When the aforementioned pharmaceutical composition is used for oral administration, it can be manufactured as a sustained-release formulation through appropriate encapsulation, enteric coating, polymer formulation, etc.

[0051] In one embodiment, the sustained-release formulation can be manufactured as a long-acting formulation.

[0052] In one embodiment, a long-acting formulation can be made by mixing polymers and lipids in appropriate proportions.

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

[0054] The pharmaceutical compositions of the present invention can be administered to a target organism in a pharmaceutically effective amount. In the present invention, the term "administration" means introducing the pharmaceutical compositions of the present invention to a target organism in a suitable manner, and the route of administration can be through a variety of oral or parenteral routes, as long as it can reach the target tissue. Examples of routes of administration include, but are not limited to, oral, intramuscular, intravenous, arterial, subcutaneous, abdominal, pulmonary, and nasal administration, and may be administered subcutaneously or orally, for example.

[0055] In this invention, the term "pharmaceutically effective amount" means an amount sufficient to prevent and / or treat cancer with a reasonable benefit / risk ratio applicable to medical use. Appropriate dosages and administration frequencies can be selected by methods known to the art, and the actual amount and frequency of administration of the pharmaceutical composition of this invention can be appropriately determined by a variety of factors such as the type of symptom to be treated, the route of administration, sex, health status, diet, age of the individual, weight, and severity of the disease.

[0056] In this invention, pharmaceutically acceptable salts mean 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. In addition, there are 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, as well as amino acid salts such as lysine, arginine, and guanidine. There are also salts of organic ions such as tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, benzyltrimethylammonium, and benzethonium, which can be used in pharmaceutical reactions, purification, and separation processes. However, the types of salts that are meant in this invention are not limited by these listed salts.

[0057] Since the ADP-ribose-conjugated peptide of the present invention has excellent anticancer activity, it can be produced not only as a pharmaceutical composition but also in the form of a functional food composition.

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

[0059] The aforementioned food composition can be manufactured as a functional food, where "functional food" is the same term as "food for special health use (FoSHU)," and refers to a food with high medical and therapeutic effects that has been processed to efficiently exhibit biological regulatory functions in addition to nutritional supply. The aforementioned functional food can be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills in order to obtain effects useful in improving cancer.

[0060] Another embodiment of the present invention is an adjunctive anticancer pharmaceutical composition that enhances reactivity to a second anticancer agent, comprising the ADP-ribose-binding peptide or a pharmaceutically acceptable salt thereof as an active ingredient.

[0061] Another embodiment of the present invention is a pharmaceutical composition for the prevention or treatment of cancer, comprising (i) the ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof, and (ii) a second anticancer agent as an active ingredient.

[0062] The above applies to ADP-ribose-bound peptides and their pharmaceutically acceptable salts.

[0063] The ADP-ribose-conjugated peptide of the present invention not only possesses anticancer effects on its own, but also exhibits excellent efficacy as an adjunct anticancer pharmaceutical composition for the purpose of enhancing responsiveness to a second anticancer agent. Therefore, the ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof can be used together with a second anticancer agent as an active ingredient in a pharmaceutical composition for the prevention or treatment of cancer.

[0064] In the present invention, the term "second anticancer agent" refers to any drug having anticancer activity other than the ADP-ribose-binding peptide of the present invention. In the present invention, the range of the second anticancer agent is not particularly limited, and a person skilled in the art can select and use an appropriate type depending on the type and stage of cancer, for purposes such as complete cure, regulation, or symptom relief. The second anticancer agent may, but is not limited to, a cytotoxic anticancer agent, a targeted anticancer agent, an immunosuppressant, or a metabolic anticancer agent.

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

[0066] Examples of alkylating agents include, but are not limited to, nitrogen mustard (e.g., cyclophosphamide, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, etc.), alkyl sulfonates (e.g., busulfan, procarbazine, etc.), nitrosoureas (e.g., carmustine, lomustine, streptozosin, etc.), and platinum-based alkylating agents (e.g., cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satoraplatin, triplatin tetranitrate, etc.). Alkylating agents can induce the destruction of cancer cells by binding to intracellular DNA and damaging the DNA structure.

[0067] The aforementioned antimetabolites include, but are 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.). Antimetabolites can induce cancer cell death by suppressing metabolism necessary for DNA replication and cell survival.

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

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

[0070] As an example, the targeted anticancer agent 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 agent that can be administered in combination with an ADP-ribose-binding peptide is a VEGF-A inhibitor. In the present invention, the VEGF-A inhibitor may be, but is not limited to, monoclonal antibodies such as bevacizumab, ranibizumab, aflibercept, and ramucirumab, or small molecule compounds such as sunitinib, pazopanib, sorafenib, and axitinib.

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

[0073] In addition, the targeted anticancer agents of the present invention also include 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 restaurtinib, ruxolitinib, and pacritinib; and MAP2-targeted anticancer agents such as cobimethinib, selumetinib, trametinib, and binimetinib. Kinase-targeted anticancer agents; including MEL4-ALK-targeted anticancer agents such as ceritibin and crizotinib, but not particularly limited in type.

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

[0075] In this invention, an immunosuppressant is a drug that activates the body's immune system to fight cancer cells. In this invention, immunosuppressants include immune checkpoint inhibitors, immunotherapy agents, anti-cancer vaccines, and antibody-drug conjugates, and the appropriate type can be selected depending on the type and stage of cancer to achieve a complete cure, control, or symptom relief of cancer.

[0076] In one embodiment, the immunosuppressant is 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 suppressor may be, but is not limited to, a PD-1 antibody such as nivolumab, pembrolizumab, cemiplimab, pidilizumab, or tripalimab; 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 immunosuppressant cancer agent may be an immunotherapy agent, and may be a CAR-T therapy agent such as tisagenlecleucel, axicabtagene ciloleucel, or a CAR-NK therapy agent, but is not limited thereto.

[0078] In the present invention, a metabolic anticancer agent refers to a drug that kills cancer cells by supplying nutrients to them or by being involved in various essential metabolic processes that contribute to the growth and survival of cancer cells. The metabolic anticancer agent may be, but is not limited to, 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.

[0079] The ADP-ribose-binding peptide of the present invention has the effect of disrupting the balance of ADP-ribose in cancer cells and enhancing the responsiveness to a second anticancer agent, and can therefore be used as an anticancer adjuvant agent. There are no particular limitations on the type of second anticancer agent used or the type of cancer. For example, the cancer may be, but is not limited to, solid tumors such as brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, stomach cancer, or ovarian cancer.

[0080] The ADP-ribose-conjugated peptide of the present invention can be administered in combination with a second anticancer agent in a form that exists independently of the second anticancer agent, or, depending on the purpose, can be administered in a state in which a physical / chemical bond has been formed with the second anticancer agent by any known method. For example, the ADP-ribose-conjugated peptide can be used in a state in which it is directly conjugated with the second anticancer agent, or in a state in which it is linked with the second anticancer agent through a known linker, and the method of application is not particularly limited as long as the ADP-ribose-conjugated peptide of the present invention acts together with the second anticancer agent to exhibit a synergistic anticancer effect.

[0081] In one specific embodiment of the present invention, when different cancer types were treated with low concentrations of bevacizumab, osimertinib, gemcitabine, and docetaxel, along with the ADP-ribose-binding peptide of the present invention, it was confirmed that the responsiveness to the anticancer drugs was enhanced in all cancer cells (Figures 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 used very effectively as an adjunct to anticancer therapy. Furthermore, it exhibits excellent anticancer activity even when treated with a second anticancer drug at low concentrations, thus minimizing the side effects that may occur with the second anticancer drug.

[0082] Another embodiment of the present invention is an adjunctive anticancer pharmaceutical composition comprising the ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof as an active ingredient, which enhances responsiveness to radiotherapy for cancer.

[0083] The ADP-ribose-bound peptides and their pharmaceutically acceptable salts are as described above.

[0084] In this invention, the term "radiotherapy for cancer" refers to a therapeutic act of irradiating cancer cells or tumor tissue with radiation for the purpose of killing cancer cells. Generally, it is a standard treatment method for controlling tumors that are inoperable or unoperable, or tumor metastases, and is based on the principle that radiation delivered to the target site causes the death of reproductive cells. In this invention, radiotherapy for cancer may be, but is not limited to, ionizing radiation therapy, electromagnetic radiation therapy, brachytherapy, or external beam radiation therapy.

[0085] The compositions comprising the ADP-ribose-binding peptide or a pharmaceutically acceptable salt thereof according to the present invention exhibit a synergistic anticancer effect when used in combination with radiotherapy, and can therefore be usefully utilized as an anticancer adjuvant or radiosensitizer to improve radiosensitivity to radiotherapy, and are not particularly limited to the types of cancer to which they can be applied. For example, the cancers may be, but are not limited to, solid tumors such as brain cancer, lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, stomach cancer, and ovarian cancer.

[0086] As one possible implementation, the solid tumor may exhibit resistance to radiotherapy. Since the anticancer effect of radiotherapy is demonstrated by the formation of DNA breaks, resistance to radiotherapy is generally determined by the mechanism that can repair DNA damage induced by radiotherapy. Many attempts have been made to suppress DNA repair mechanisms as a way to synergistically enhance the anticancer efficacy of radiotherapy, and if the repair of damaged DNA strands is blocked, the sensitivity of radiotherapy may increase. The two main forms of DNA damage are SSB (Single Strand Breaks) and DSB (Double Strand Breaks). Therefore, it can be explained within the categories of two repair pathways targeting SSB and DSB. BER (Base Excision Repair) is one of the various pathways involved in the repair of selected types of DNA SSBs.

[0087] PARP1 plays a crucial role in the DNA SSB BER through a process known as ADP-ribosylation. In the nucleus, PARP1 senses damage to SSB DNA and recruits DNA repair complexes to the SSB site via ADP-ribosylation for repair. Excessive accumulation of poly-ADP-ribose synthesized through ADP-ribosylation mediated by PARP-1 ultimately leads to cell death. To prevent this, cancer cells activate the degradation of poly-ADP-ribose through proteasomes such as PARG and ARH3, thereby activating survival signaling activity. The inventors have focused on the fact that the accumulation of ADP-ribose and ADP-ribose polymers in cancer cells can act as a mediator to disrupt these biochemical survival mechanisms in cancer cells and can be utilized as an important anti-cancer adjuvant to overcome radiotherapy resistance.

[0088] In one specific embodiment of the present invention, it was confirmed that when different cancer types were treated with low-dose radiation therapy in combination with the ADP-ribose-binding peptide of the present invention, the responsiveness 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 used very effectively as an adjunct to anti-cancer treatment. Furthermore, it exhibits excellent anti-cancer activity even when irradiated at tolerance doses, thus minimizing the side effects that may occur due to radiation.

[0089] Embodiments of the present invention can be modified into various other forms, and the scope of the invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more fully explain the invention to a person of average skill in the art. Moreover, throughout the specification, the phrase "includes" a component does not exclude other components unless specifically contradicted, but rather means that other components may be further included.

[0090] [Modes for carrying out the invention] The configuration and effects of the present invention will be explained in more detail below through examples. These examples are solely for illustrative purposes and do not limit the scope of the present invention.

[0091] Examples 1-14. Production of ADP (adenosine diphosphate)-ribose-conjugated peptides ADP-ribose-conjugated peptides, as described in Examples 1 to 14, were synthesized from WWE domains present in various types of proteins and used in the experiments. Specific information on the peptides used is shown in Table 1 below.

[0092] [Table 1]

[0093] Furthermore, cell-penetrating peptides were attached to the N-terminus of the peptides of Examples 1 to 14 to produce 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 within cancer cells The peptides in Examples 1 to 28 of the present invention are designed to inhibit the activity of poly-ADP-ribose-degrading enzymes. In Experimental Example 1, cell experiments were conducted to confirm whether the degradation of poly-ADP-ribose was inhibited by each peptide, leading to its accumulation in cancer cells.

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

[0097] The upper left of Figure 1 and the lower right of Figure 2 show the fold change in the increased amount of ADP-ribose in the U-87MG cells by the peptide treatment of Example 1 or 8 compared to the control group, indicating that the amount of ADP-ribose significantly increased in a concentration-dependent manner for both of the two peptides treated compared to the non-treated group ( ** p<0.001).

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

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

[0100] 1-3. Changes in intracellular ADP-ribose levels in Aspc-1 5 x 10 5 Aspc-1 cells were cultured for 24 hours at 37°C under 5% CO2 conditions in RPMI-1640 medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin. The cells were divided into two groups: one group untreated with the example peptide, and the other treated with 0.2, 1, 2, 4, 8, 16, and 32 μM of the Example 3 peptide (SEQ ID NO: 3). The culture medium was removed from the cultured cells, and they were treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect and analyze ADP-ribose.

[0101] The lower left of Figure 1 and the upper right of Figure 3 show the multiplicative increase in ADP-ribose compared to the control group in Aspc-1 cells treated with the peptides of Example 3 or Example 10, indicating a significant concentration-dependent increase in ADP-ribose compared to the untreated group. ** p<0.001).

[0102] 1-4. Changes in intracellular ADP-ribose levels in Hep G2 cells 5 x 10 5 Hep G2 cells were cultured for 24 hours at 37°C under 5% CO2 conditions in EMEM medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin. The cells were divided into two groups: one group received no treatment with the example peptide, and the other received 0.2, 1, 2, 4, 8, 16, and 32 μM of the Example 4 peptide (SEQ ID NO: 4). The culture medium was removed from the cultured cells, and the cells were treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect and analyze ADP-ribose.

[0103] The lower right of Figure 1 and the lower left of Figure 3 show the multiplicative increase in ADP-ribose compared to the control group in Hep G2 cells treated with the peptides of Example 4 or Example 11, indicating a significant concentration-dependent increase in ADP-ribose compared to the untreated group.** p<0.001).

[0104] 1-5. Changes in intracellular ADP-ribose levels in MDA-MB-231 5 x 10 5 Individual MDA-MB-231 cells were cultured for 24 hours at 37°C under 5% CO2 conditions in Leibovitz's L-15 medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin. The cells were divided into two groups: one group untreated with the example peptide, and the other treated with 0.2, 1, 2, 4, 8, 16, and 32 μM of the Example 5 peptide (SEQ ID NO: 5). The culture medium was removed from the cultured cells, and they were treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect and analyze ADP-ribose.

[0105] The upper left of Figure 2 and the lower right of Figure 3 show the multiplicative increase in ADP-ribose compared to the control group in MDA-MB-231 cells treated with the peptides of Example 5 or Example 12, indicating a significant concentration-dependent increase in ADP-ribose compared to the untreated group. ** p<0.001).

[0106] 1-6. Changes in intracellular ADP-ribose levels in HCT116 5 x 10 5 HCT116 cells were cultured for 24 hours at 37°C under 5% CO2 conditions in McCoy's 5A medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin. The cells were divided into two groups: one group received no treatment with the example peptide, and the other received 0.2, 1, 2, 4, 8, 16, and 32 μM of the Example 6 peptide (SEQ ID NO: 6). The culture medium was removed from the cultured cells, and they were treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect and analyze ADP-ribose.

[0107] The upper right of Figure 2 and the left side of Figure 4 show the multiplicative increase in ADP-ribose compared to the control group in HCT116 cells treated with the peptides of Example 6 or Example 13, indicating a significant concentration-dependent increase in ADP-ribose compared to the untreated group. ** p<0.001).

[0108] 1-7. Changes in intracellular ADP-ribose levels in Caki-1 5 x 10 5 Caki-1 cells were cultured for 24 hours at 37°C under 5% CO2 conditions in McCoy's 5A medium containing 10% FBS, 100 units / ml penicillin, and 100 μg / ml streptomycin. The cells were divided into two groups: one group received no treatment with the example peptide, and the other received 0.2, 1, 2, 4, 8, 16, and 32 μM of the Example 7 peptide (SEQ ID NO: 7). The culture medium was removed from the cultured cells, and they were treated with RIPA buffer and 1% SDS. The prepared supernatant was used for ELISA analysis to detect and analyze ADP-ribose.

[0109] The lower left of Figure 2 and the right side of Figure 4 show the multiplicative increase in ADP-ribose compared to the control group in Caki-1 cells treated with the peptides of Example 7 or Example 14, indicating a significant concentration-dependent increase in ADP-ribose compared to the untreated group. ** p<0.001).

[0110] Experimental Example 2: Changes in cancer cell survival rate after peptide treatment of the example. Cells maintain biochemical homeostasis and a balance between the production and degradation of ADP-ribose. Because cancer cells divide continuously and grow rapidly, a disruption of this balance can significantly impact their survival compared to normal cells.

[0111] According to the results of Experimental Example 1, when cancer cells are treated with the peptides of the present invention, the amount of intracellular ADP-ribose increases significantly, which can disrupt the homeostatic balance of cancer cells. Therefore, in Experimental Example 2, the survival rate of cancer cells treated with the peptides of Examples 1 to 28 was measured.

[0112] 2-1. Changes in cell viability in U-87MG cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3 After culturing individual U-87MG cells at 37°C and 5% CO2 for 24 hours, the cells were either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. The cells were then cultured again at 37°C and 5% CO2 for another 24 hours. 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0113] The upper left of Figure 5 and the upper right of Figure 8 are representative micrographs of U-87MG cells treated with the peptides of Examples 1, 15, 8, and 22, respectively, and untreated groups. In common, the untreated groups showed rapid growth in the U-87MG cells, while the groups treated with the example peptides of the present invention showed suppressed growth and death of the U-87MG cells. In particular, complete elimination of cancer cells was confirmed in the groups treated with the peptides of Examples 15 and 22, which had cell-penetrating peptides (CPPs) attached.

[0114] 2-2. Changes in cell viability in H1975 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3H1975 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. After further 24 hours of incubation at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0115] The upper right of Figure 5 and the upper left of Figure 9 are representative micrographs of H1975 cells treated with the peptides of Examples 2, 16, 9, and 23, respectively, and untreated groups. In common, the untreated groups showed a morphology of rapidly growing H1975 cells, while the groups treated with the example peptides of the present invention showed a morphology of suppressed growth and death of H1975 cells. In particular, complete elimination of cancer cells was confirmed in the groups treated with the peptides of Examples 16 and 23, which had CPP attached.

[0116] 2-3. Changes in cell survival rate in Aspc-1 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3 After culturing individual Aspc-1 cells at 37°C and 5% CO2 for 24 hours, the cells were either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. The cells were then cultured again at 37°C and 5% CO2 for another 24 hours. Finally, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0117] The upper left of Figure 6 and the upper right of Figure 9 are representative micrographs of Aspc-1 cells treated with the peptides of Examples 3, 17, 10, and 24, respectively, and untreated groups. In common, the untreated groups showed a morphology of rapidly growing Aspc-1 cells, while the groups treated with the example peptides of the present invention showed a morphology of suppressed growth and death of Aspc-1 cells. In particular, complete elimination of cancer cells was confirmed in the groups treated with the peptides of Examples 17 and 24, which have the cell-permeable peptide CPP attached.

[0118] 2-4. Changes in cell survival rate in Hep G2 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3 Hep G2 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0119] The upper right of Figure 6 and the upper left of Figure 10 are representative micrographs of Hep G2 cells treated with the peptides of Examples 4, 18, 11, and 25, respectively, and untreated groups. In common, the untreated groups showed rapid growth in Hep G2 cells, while the groups treated with the peptides of the present invention showed suppressed growth and cell death. In particular, complete cell death was confirmed in the groups treated with the peptides of Examples 18 and 25, which had the cell-permeable peptide CPP attached.

[0120] 2-5. Changes in cell viability in MDA-MB-231 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3After culturing individual MDA-MB-231 cells at 37°C under 5% CO2 conditions for 24 hours, the cells were either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. The cells were then cultured again at 37°C under 5% CO2 conditions for another 24 hours. Finally, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0121] The upper left of Figure 7 and the upper 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 untreated groups. In common, the untreated groups showed rapid growth of MDA-MB-231 cells, while the groups treated with the example peptides of the present invention showed suppressed growth and cell death. In particular, complete cell death was confirmed in the groups treated with the peptides of Examples 19 and 26, which had CPP attached.

[0122] 2-6. Changes in cell viability in HCT116 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3 HCT116 cells were cultured at 37°C and 5% CO2 for 24 hours, after which they were either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. After another 24 hours of incubation at 37°C and 5% CO2, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0123] The upper right of Figure 7 and the upper left of Figure 11 show representative micrographs of HCT116 cells treated with the peptides of Examples 6, 20, 13, and 27, respectively, and untreated groups. In common, the untreated groups showed rapid growth in the HCT116 cells, while the groups treated with the example peptides of the present invention showed suppressed growth and cell death. In particular, complete cell death was confirmed in the groups treated with the peptides of Examples 20 and 27, which had the cell-permeable peptide CPP attached.

[0124] 2-7. Changes in cell survival rate in Caki-1 cells after treatment with ADP-ribose-binding peptide. 3 x 10 in a 96-well plate 3 Caki-1 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then either left untreated or treated with 16 μM peptides from Examples 1-28, respectively. After further 24 hours of incubation at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0125] The upper left of Figure 8 and the upper right of Figure 11 are representative micrographs of Caki-1 cells treated with the peptides of Examples 7, 21, 14, and 28, respectively, and untreated groups. In common, the untreated groups showed a morphology of rapidly growing Caki-1 cells, while the groups treated with the example peptides of the present invention showed a morphology of suppressed growth and death of Caki-1 cells. In particular, complete elimination of cancer cells was confirmed in the groups treated with the peptides of Examples 21 and 28, which had CPP attached.

[0126] 2-8. Changes in cell survival rates in SNU-1 and OVCAR-3 cells after treatment with ADP-ribose-binding peptides. 3 x 10 in a 96-well plate 3After culturing individual SNU-1 or OVCAR-3 cells at 37°C and 5% CO2 for 24 hours, the cells were either left untreated or treated with 16 μM peptides from Examples 15-28, respectively. The cells were then cultured for a further 96 hours at 37°C and 5% CO2. 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0127] As a result, we confirmed that the groups treated with the peptides from Examples 15-28 each had almost complete elimination of cancer cells in both SNU-1 and OVCAR-3 cells (Figure 12).

[0128] Experimental Example 3: Changes in cancer cell survival rate after combined treatment with the peptide from the example and a low concentration of anticancer drug. The anticancer effects of existing anticancer drugs, such as the reduction in cancer cell survival, can be synergistically mediated by ADP-ribose signaling. Therefore, it was expected that treating cancer cells with existing anticancer drugs to induce ADP-ribose accumulation would result in a synergistic anticancer effect even when the existing anticancer drugs were treated at concentrations below the required level. As confirmed in Experimental Example 1, the peptide of the present invention significantly increases the amount of ADP-ribose in cancer cells. Therefore, in Experimental Example 3, we aimed to confirm whether a synergistic anticancer effect would be observed when the peptide of the present invention was used in combination with a low concentration of anticancer drug.

[0129] 3-1. Changes in cell survival rate in U-87MG cells after combined treatment with the example peptide and low-concentration bevacizumab. 3 x 10 in a 96-well plate 3After culturing individual U-87MG cells at 37°C and 5% CO2 for 24 hours, they were treated with 18 mM bevacizumab alone or in combination with peptides from Examples 1-14 at concentrations of 0.2, 1, or 8 μM. The cells were then cultured again at 37°C and 5% CO2 for a further 24 hours. 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

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

[0131] 3-2. Changes in cell survival rate in 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 under 5% CO2 conditions for 24 hours, and then treated with 1 nM osimertinib alone or in combination with peptides from Examples 1-14 at concentrations of 0.2, 1, or 8 μM. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

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

[0133] 3-3. Changes in cell survival rate in Aspc-1 cells after combined treatment with the example peptide and low-concentration gemcitabine. 3 x 10 in a 96-well plate 3 After culturing individual aspc-1 cells at 37°C and 5% CO2 for 24 hours, they were treated with 1 μM gemcitabine alone or in combination with peptides from Examples 15-28 at concentrations of 0.2, 1, or 8 μM. The cells were then cultured again at 37°C and 5% CO2 for another 24 hours. 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

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

[0135] 3-4. Changes in cell survival rate in MDA-MB-231 cells after combined treatment with the example peptide and low-concentration docetaxel. 3 x 10 in a 96-well plate 3 After culturing individual MDA-MB-231 cells at 37°C and 5% CO2 for 24 hours, they were treated with 50 μM docetaxel alone or in combination with peptides from Examples 15-28 at concentrations of 0.2, 1, or 8 μM. The cells were then cultured again at 37°C and 5% CO2 for a further 24 hours. 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

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

[0137] Experimental Example 4: Changes in cancer cell survival rate after combined treatment with the peptide and radiation described in the example. While radiation therapy can be expected to have an anti-cancer effect through cell death caused by damage to genetic material, cancer cells overcome this by continuously repairing the DNA strand 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, could be continuously accumulated, a synergistic anti-cancer effect would be observed even when radiation is applied at a tolerance dose. As confirmed in Experimental Example 1, the peptide of the present invention significantly increases the amount of ADP-ribose in cancer cells. Therefore, in Experimental Example 4, we aimed to confirm whether a synergistic anti-cancer effect would be shown when the peptide of the present invention was used in combination with radiation at a tolerance dose.

[0138] 4-1. Changes in cell viability in H1975 cells after combined radiation treatment with example peptides and tolerance doses. 3 x 10 in a 96-well plate 3 H1975 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then treated with 2 Gy of radiation alone or in combination with 1.6 or 3.2 μM of peptides SEQ ID NOs. 1-14. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0139] As a result, when H1975 cells were treated with a 2 Gy dose of radiation alone, approximately 76% of cancer cells showed resistance and survived 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 cancer cells was significantly reduced even with radiation at a tolerance dose. ** p<0.001, *** p<0.001; left side of Figure 15).

[0140] 4-2. Changes in survival rate of Aspc-1 cells after combined radiation treatment with example peptides and tolerance doses. 3 x 10 in a 96-well plate 3 Aspc-1 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then treated with 2 Gy of radiation alone or in combination with 1.6 or 3.2 μM of peptides SEQ ID NOs. 1-14. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0141] As a result, when Aspc-1 cells were treated with a 2 Gy dose of radiation alone, approximately 86% of cancer cells showed resistance and survived 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 cancer cells was significantly reduced even with radiation at a tolerance dose. ** p<0.001, *** p<0.001; right side of Figure 15).

[0142] 4-3. Changes in cell survival rate in MDA-MB-231 cells after combined radiation treatment with example peptides and tolerance doses. 3 x 10 in a 96-well plate 3Individual MDA-MB-231 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then treated with 2 Gy of radiation alone or in combination with 1.6 or 3.2 μM of peptides of sequence numbers 15-28. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

[0143] As a result, when MDA-MB-231 cells were treated with a 2 Gy dose of radiation alone, approximately 86% of cancer cells showed resistance and survived 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 cancer cells was significantly reduced even with radiation at a tolerance dose. ** p<0.001, *** p<0.001; left side of Figure 16).

[0144] 4-4. Changes in survival rate of Caki-1 cells after combined radiation treatment with example peptides and tolerance doses. 3 x 10 in a 96-well plate 3 Caki-1 cells were cultured at 37°C under 5% CO2 conditions for 24 hours, and then treated with 2 Gy of radiation alone or in combination with 1.6 or 3.2 μM of peptides of sequence numbers 15-28. After further 24 hours of culture at 37°C under 5% CO2 conditions, 10 μl of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide reagent was added to each well and allowed to react for 1 hour. After removing the reagent, 200 μl of dimethyl sulfoxide was added to each well, and cell viability was confirmed by measuring the absorbance.

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

[0146] Experimental Example 5: Comparison and Verification of Anti-cancer Efficacy of Peptides Based on Administration Route Using an Animal Model 5-1. Changes in tumor volume in animal models injected subcutaneously with example peptides. 5-week-old balb / c nude mice were given aspc-1 cells (1 × 10⁻¹⁶). 7 The peptide was injected into the posterior flank of mice and they were divided into 15 groups: an untreated control group and groups receiving subcutaneous injections of the peptides from Examples 15-28. The tumor volume was approximately 150 mm². 3 When the tumors had grown to a certain stage, each example peptide was administered subcutaneously at a dose of 20 mg / kg three times a week. Tumor size was measured using a digital kerifer, and the changes in tumor volume were compared between the groups.

[0147] As a result, the final tumor volume in the control group after the last dose was approximately 3136 mm³. 3 Although the tumors grew significantly, we confirmed that tumor growth was significantly suppressed in all groups where the peptides from Examples 15-28 were injected subcutaneously. ** p<0.001; Figure 17).

[0148] Figure 18 shows representative tumor images obtained after autopsy in all groups. Compared to the control group, it was observed that tumor tissue growth was significantly suppressed in all groups that received subcutaneous injection of the peptide of the present invention.

[0149] 5-2. Changes in tumor volume in animal models administered via oral route using example peptides. 5-week-old balb / c nude mice were given aspc-1 cells (1 × 10⁻¹⁶). 7 The peptide was injected into the posterior flank of mice and they were divided into 15 groups: an untreated control group and groups that received oral administration of the peptides from Examples 1-14. The tumor volume was approximately 150 mm². 3 When the tumors had grown to a certain stage, each example peptide was administered orally at a dose of 20 mg / kg five times a week. Tumor size was measured using a digital chelist, and the changes in tumor volume were compared between the groups.

[0150] As a result, the final tumor volume in the control group after the last dose was approximately 3517 mm³. 3 Although the tumors grew significantly, we confirmed that tumor growth was significantly suppressed in all groups that received oral administration of the peptides from Examples 1 to 14. ** p<0.001; Figure 19).

[0151] Figure 20 shows representative tumor images obtained after autopsy in all groups. Compared to the control group, it was observed that tumor tissue growth was significantly suppressed in all groups that received oral administration of the peptide of the present invention.

[0152] Experimental Example 6: Confirmation of Cytotoxicity of Example Peptides in Normal Cells Next, we further investigated 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 Sequence ID No. 7 was used as a representative example peptide of the present invention.

[0153] First, fill a 96-well plate with 5 x 10 3 After inoculating each normal cell, they were cultured in DMEM medium at 37°C under 5% CO2 conditions for 24 hours. Each well was divided into an untreated group and a group treated with the peptide of SEQ ID NO: 7 (25, 50, and 100 μM, respectively), and the experiment was carried out accordingly.

[0154] The experimental results showed no significant difference between the untreated control group and any of the groups treated with the peptide (24, 48, or 72 hours after treatment) (Figures 21 and 22). Therefore, it was confirmed that the peptide of the present invention exhibits potent anticancer activity in cancer cells while showing no cytotoxicity in normal cells, thus demonstrating excellent efficacy for anticancer applications.

[0155] From the above description, those skilled in the art in which the present invention pertains should understand that the present invention can be implemented in other specific forms without altering its technical idea or essential features. In this regard, it should be understood that the embodiments described above are illustrative and not limiting in all respects. The scope of the present invention should be interpreted as encompassing all modified or altered forms derived from the meaning and scope of the claims, which are described later in the detailed description above, and their equivalent concepts.

Claims

1. A separated ADP (adenosine diphosphonate)-ribose-linked peptide consisting of the amino acid sequence of SEQ ID NO:

11.

2. The ADP-ribose-conjugated peptide according to claim 1, wherein the peptide further comprises a cell-penetrating peptide at its N-terminus, C-terminus, or both ends.

3. The ADP-ribose-conjugated peptide according to claim 2, wherein the peptide has the amino acid sequence of SEQ ID NO:

25.

4. An ADP (adenosine diphosphonate)-ribose-linked peptide consisting of one amino acid sequence selected from the group consisting of SEQ ID NOs: 4-10 and 12-14.

5. The ADP-ribose-conjugated peptide according to claim 4, wherein the peptide further comprises a cell-penetrating peptide at its N-terminus, C-terminus, or both ends.

6. The ADP-ribose-binding peptide according to claim 5, having one amino acid sequence selected from the group consisting of SEQ ID NOs: 18-24 and 26-28.

7. A polynucleotide encoding the ADP-ribose-linked peptide described in any one of claims 1 to 6.

8. A vector comprising the polynucleotide described in claim 7.

9. A transformant comprising the polynucleotide described in claim 7.

10. A pharmaceutical composition for the prevention or treatment of cancer, comprising an ADP-ribose-conjugated peptide or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, as an active ingredient.

11. The pharmaceutical composition for the prevention or treatment of cancer according to claim 10, 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, colorectal cancer, kidney cancer, stomach cancer, and ovarian cancer.

12. The pharmaceutical composition for the prevention or treatment of cancer according to claim 10, wherein the composition is administered subcutaneously or orally.

13. An adjunct anticancer pharmaceutical composition comprising an ADP-ribose-binding peptide or a pharmaceutically acceptable salt thereof as an active ingredient, which enhances reactivity to a second anticancer agent.

14. The anticancer agent is a cytotoxic anticancer agent, a targeted anticancer agent, or a combination thereof, as described in claim 13, for use as an adjunct anticancer pharmaceutically.

15. The anticancer adjunct pharmaceutical composition according to claim 13, wherein the cancer targeted by the second anticancer agent 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.

16. (i) an ADP-ribose-conjugated peptide according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and (ii) Contains a second anticancer drug as an active ingredient, Pharmaceutical compositions for the prevention or treatment of cancer.

17. An adjunct anticancer pharmaceutical composition comprising an ADP-ribose-binding peptide or a pharmaceutically acceptable salt thereof as an active ingredient, which enhances responsiveness to radiotherapy for cancer treatment.

18. The anti-cancer adjunct pharmaceutical composition according to claim 17, wherein the cancer targeted by the radiotherapy 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, stomach cancer, and ovarian cancer.

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