KR101670770B1 - Peptide analog binding to polo-box domain of polo-like kinase-1 and pharmaceutical composition for anti-cancer containing thereof - Google Patents

Abstract

The present invention relates to a novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, and more particularly to a novel peptide analogue, or a stereoisomer or a pharmaceutically acceptable salt thereof, for an anticancer composition. The novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, is characterized by high affinity and selective binding to the poloxane domain of polo-like phosphorylase-1, and inhibits the activity of polo-like phosphorylase-1 And can be utilized as an excellent anticancer composition.

Description

[0001] The present invention relates to a peptide analogue specifically binding to the polo box domain of polo-like kinase-1 and to an anticancer composition comprising the peptide analogue and a composition for anti-cancer comprising the polo-box domain of polo-like kinase- }

The present invention relates to novel peptide analogs (peptidomimetic), or stereoisomers or pharmaceutically acceptable salts thereof and uses thereof. More particularly, the present invention relates to novel peptide analogs, or stereoisomers or pharmaceutically acceptable salts thereof, and their anticancer uses.

As a cause of cancer, it is a cancer suppressor gene that blocks the production of cancer cells by inhibiting the abnormal proliferation of cells due to abnormal activation of cancer-causing cancer gene, or by inhibiting the abnormal proliferation of cells or by killing certain cells by operating a cell death program However, even if a cell has an abnormally activated cancer gene, if the cancer suppressor gene shows normal activity, the cell will die without cancer. Therefore, in order to become a cancer cell, inactivation of a cancer-suppressing gene as well as activation of a carcinogenesis gene must occur simultaneously in one cell.

Recently, there has been a fierce competition for discovering therapeutic targets and studying the functions of genes related to the generation and treatment of cancer in the world. With the activation of the genome research, studies on human gene DNA chip or proteome analysis have been actively conducted, and a large number of genes related to cancer have been discovered. Therefore, a list of many genes and related databases have been established, but most of these genes Biological function and cancer relatedness have not yet been studied or are uncertain. Therefore, there is considerable difficulty in finding genes that can effectively treat cancer, in addition to actual cancer-related or diagnosis and utilization as target genes. Therefore, in addition to the cancer-related genes identified so far, it is necessary to discover new genes.

In the meantime, three of the main methods of treating cancer are surgery, pharmacotherapy, and radiotherapy. Drug therapy is associated with less pain associated with treatment, and even after surgery, As relapse is relatively small, expectations are gathering. Therefore, many anticancer drugs have been developed and used to cope with them. Most of these anticancer drugs exhibit anticancer effects by selectively killing cells that are actively dividing in consideration of abnormal growth of cancer. Such anticancer drugs have serious problems such as immune cells and hair follicle cells, which are actively dividing cells in the human body, and they are accompanied with serious side effects, so that they can not be used for a long time. In addition, endoscopic mucosal resection has been used for the treatment of stomach cancer, including lymphadenectomy, endoscopic mucosal resection, and laparoscopic gastrectomy. Endoscopic mucosal resection is performed by injecting saline into the gastric mucosa around the cancerous lesions The purpose of this study was to evaluate the efficacy and safety of gastric resection for early gastric cancer in patients with early gastric cancer. There is a limit.

Inhibition of specific protein kinases overexpressed in human tumor tissues has been established as a treatment modality that can identify potent inhibitors over the past decade. The polo-like phosphorylase-1 is a protein consisting of a kinase domain located at the N-terminus of the protein and a pollo-box domain located at the C-terminus. The kinase domain phosphorylates the serine or threonine of the target protein, It recognizes the target protein that contains threonine. Polo-like phosphorylase-1 is known to be overexpressed in cancer cells, and a chemical antagonist that specifically inhibits polo-like phosphorylase-1 has been reported to specifically induce apoptosis in cancer cells. Therefore, polo-like phosphorylase-1 is important as a target for the development of anticancer drugs and many candidate substances have been developed. However, most of the chemical antagonists for polo-like phosphorylase-1 target the kinase domain and have a disadvantage in that the chemical antagonist for the kinase domain is less selective because of the similar structure of the kinase domain of eukaryotes.

Therefore, the present inventors synthesized peptide analogues having high affinity and selectively binding to polo box domain of polo-like phosphorylase-1 and can use them as powerful anticancer agents.

Korean Patent No. 10-0740893

Therefore, an object of the present invention is to provide a novel peptide analogue which has high affinity and selectively binds to the poloxane domain of polo-like kinase-1.

Another object of the present invention is to provide an anticancer composition comprising the novel peptide analogue or a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the object of the present invention, the present invention provides a novel peptide analogue having high affinity and selective binding to the polo box domain of polo-like phosphorylase-1, and the novel peptide analogue or its stereoisomer Or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the polo box domain of polo-like phosphorylase-1 may comprise the amino acid sequence of SEQ ID NO: 1.

In one embodiment of the invention, the phosphorylated peptide binding site is selected from the group consisting of 414 tryptophan, 415 valine, 416 aspartic acid, 417 tyrosine residues of the poloxane domain protein of polo-like phosphorylase-1 consisting of the amino acid sequence of SEQ ID NO: , The 481th tyrosine, and the 485th tyrosine.

In one embodiment of the present invention, the anticancer composition may contain a novel peptide analogue, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at a concentration of 1 to 500 μM.

In one embodiment of the present invention, the anticancer composition may inhibit the activity of polo-like phosphorylase-1.

The novel peptide analogue of the present invention, or its stereoisomer or pharmaceutically acceptable salt, can exhibit an excellent anti-cancer effect through a mechanism of inhibiting the activity of polo-like phosphorylase-1, Can be used.

Figure 1 shows the nomenclature of the novel peptide analogs synthesized in the present invention in accordance with substituents.
FIG. 2 is a graph showing the poloxane domain binding assay results of the ELISA-based polo-like phosphorylase-1 of the novel peptide analog synthesized in the present invention.
3 is a graph showing cytotoxicity of the novel peptide analog synthesized in the present invention.
4 is a photograph showing the results of cell infusion into cancer cells of the novel peptide analog synthesized in the present invention.
5 is a graph showing the effect of inhibiting polo-like phosphorylase-1 activity of the novel peptide analog synthesized in the present invention.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention provides a novel peptide analogue having the structure of the following formula (1).

[Chemical Formula 1]

In Formula 1,

And may include all carboxylic acid derivatives having an aromatic ring at the N-terminus.

The present invention also provides stereoisomers or salts, preferably pharmaceutically acceptable salts, having the structure of Formula 1 above. The pharmaceutically acceptable salts refer to salts suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation and side effects, etc., within the purview of pure medical judgment. Such pharmaceutically acceptable salts are well known in the art (SM Berge et < RTI ID = 0.0 > al ., 1977, J. Parmaceutical Sciences , 66: 1). The salt can be prepared in situ during the final isolation, purification and synthesis of the derivative compound of the present invention or separately by reacting with an inorganic base or an organic base. As the pharmaceutically acceptable salt, when the derivative compound of the present invention contains an acidic group, it may form a salt with a base. Such salts include, for example, a lithium salt, a sodium salt, Salts with alkali metals such as potassium salts; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; And salts with basic amino acids such as lysine or arginine. In addition, when the derivative compound of the present invention contains a basic group in the molecule, an acid addition salt can be formed. Examples of such an acid addition salt include, but are not limited to, inorganic acids such as hydrohalic acid , Hydroiodic acid or hydrochloric acid), salts with nitric acid, carbonic acid, sulfuric acid or phosphoric acid; Salts with lower alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.

The polo-like phosphorylase-1 is a protein consisting of a kinase domain located at the N-terminus of the protein and a pollo-box domain located at the C-terminus. The kinase domain phosphorylates the serine or threonine of the target protein, It recognizes the target protein that contains threonine. The novel peptide analogues of the present invention are characterized in that the novel compounds of the present invention have high affinity and selectively bind to the polloxane domain of polo-like phosphorylase-1 and have an antitumor activity through the inhibition activity of polo- Can be derived.

More specifically, the site of the pollo-box domain of polo-like phosphorylase-1 to which the novel peptide analog of the present invention can bind includes the 414th tryptophan, the 415th valine , The 416th aspartic acid, the 417th tyrosine, the 481th tyrosine, and the 485th tyrosine. The polo box domain of polo-like phosphorylase-1 may be composed of the amino acid sequence shown in SEQ ID NO: 1, and the amino acid sequence of SEQ ID NO: 1 is encoded by the nucleotide sequence shown in SEQ ID NO: 2. In addition, the novel peptide analogues provided in the present invention exist in the form of a complex in which a peptide and a compound are bonded to each other, and the specific chemical structural formula thereof is as described above.

The present inventors have confirmed that the novel peptide analogues of the present invention have an activity of specifically inhibiting or reducing the activity of polo-like phosphorylase-1. These results show that the novel peptide analogues of the present invention, Of the present invention can be used as an anticancer agent. As described above, when polo-like phosphorylase-1 is overexpressed in cancer cells and its relationship with the tumor is known, when its activity is suppressed or its expression is decreased, It can induce apoptosis of cancer cells and induce anticancer activity.

Accordingly, the present invention can provide an anticancer composition comprising the novel peptide analogue of the present invention as an active ingredient.

The anticancer composition according to the present invention may be used as a pharmaceutical composition for preventing and treating cancer, and the pharmaceutical composition may further include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans. Pharmaceutically acceptable carriers include, for example, carriers for oral administration such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like, water for parenteral administration such as water, suitable oils, saline, aqueous glucose and glycols And may further contain stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers can be found in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995). The pharmaceutical composition according to the present invention, together with a pharmaceutically acceptable carrier as described above, may be formulated into a suitable form according to a method known in the art. That is, the pharmaceutical composition of the present invention can be prepared in various parenteral or oral administration forms according to known methods, and isotonic aqueous solutions or suspensions are preferred for injection formulations typical of parenteral administration formulations. The injectable formulations may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. For example, each component may be formulated for injection by dissolving in saline or buffer. Formulations for oral administration also include, but are not limited to, powders, granules, tablets, pills, and capsules.

The pharmaceutical composition formulated as described above may be administered in an effective amount through various routes including oral, transdermal, subcutaneous, intravenous, or muscular. The term " effective amount " as used herein refers to an amount that shows a preventive or therapeutic effect when administered to a patient. The dosage of the pharmaceutical composition according to the present invention can be appropriately selected depending on the route of administration, subject to be administered, age, gender, individual difference, and disease state. Preferably, the pharmaceutical composition of the present invention may contain the active ingredient in an amount of 1 to 10000 μg / kg body weight / day, more preferably 10 to 1000 mg / kg body weight, / day, which may be repeated several times a day. The anticancer composition of the present invention may also be administered in combination with a known compound having an effect of preventing, ameliorating or treating cancer.

The novel peptide analogs of the present invention may be used as anticancer agents, but the present invention is not limited thereto. Examples of the types of cancer include gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, Ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, and the like.

Furthermore, the novel peptide analogue, which is an active ingredient contained in the composition of the present invention, may be contained in the composition at a concentration of 1 to 500 μM, and if the concentration is outside this range, the desired effect may not be obtained.

In other words, the inhibitory effect of polokine-like kinase-1 (PLK-1 kinase) may be insufficient when it is contained at less than 1 μM, whereas if it is contained in excess of 500 μM, The effect can not be obtained, which is not economical. Therefore, it is preferable to contain it within the above-described range.

Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.

< Example  1>

Novel compounds having anticancer activity ( Peptides  Synthesis of

The present inventors used Rink amide resin loaded at 0.61 mmol / g to synthesize the peptide analog of the present invention and synthesized by Fmoc (Fluorenylmethyloxycarbonyl) Solid Phase Peptide Synthesis (SPPS). Before the synthesis, the resin was swollen in N, N-dimethylforamide (DMF) for 45 minutes. To extend the peptide sequence, Fmoc amino acid and benzoamino acid analogue corresponding to the amino acid and aromatic analogue were dissolved in 2 ml of DMF solution (1-O-Benzotriazole-N, N ', N'-tetramethyluronium, HBTU) (5.0 g of benzotriazole-N, N, N'N'-tetramethyluronium hexafluorophosphate eq), 1-hydroxybenzotriazole (HOBt) (5.0 eq) and N, N-diisopropylethylamine (DIEA) (10.0 eq) And then activated for 2 minutes.

Then, the activated solution was mixed with the resin and the binding reaction was performed for 1 hour. After washing the resin with DMF, the Fmoc protecting group was removed by 20% piperidine in DMF. The resin was then washed again and then reacted with Fmoc-protected amino acids according to their respective amino acid sequences. After synthesis of the entire amino acid sequence was completed, the resin was washed with DMF, methanol, dichloromethane and ether and then dried in vacuo. The synthesized peptides were separated from the resin using 5% triisopropylsilane (TIS) and trifluoroacetic acid (TFA) containing 5% water. Peptide analogs isolated from the resin were precipitated with cold ether and then filtered. The peptide was then purified by reverse-phase (RP) HPLC using a Vydac _C18 column. The purity of the peptide was measured by reversed-phase HPLC and the molecular weight of the final peptide was measured by MALDI-TOF MS (matrix-assisted laser desorption ionization-time-of-flight mass spectrometry) and the name of the peptide analogue according to the benzoic acid analog used As shown in Fig.

The analogs in Figure 1 were synthesized using the above method. However, the last residue analogs used the compounds described below instead of Fmoc-beta-Ala-OH.

Cyclohexanecarboxylic acid in case of AB103-1, 4-propylbenzoic acid in case of AB103-3, 4-methanoylbenzoic acid in case of AB103-5, 4-propoxybenzoic acid in the case of AB103-6, 4- (methylamino) benzoic acid in the case of AB103-8, 4- (methylamino) benzoic acid in the case of AB103-9, 4- (methylamino) benzoic acid in the case of AB103-10, 1,4- Naphthalene decarboxylic acid, 6-hydroxy-1-naphthoic acid in the case of AB103-13, AB103-14 in the case of AB103-14, -15, hexanoic acid was used.

&Lt; Example 2 >

Measurement of the binding force of the peptide analogue with the pollo-box domain of polo-like phosphorylase-1

The present inventors used an enzyme-linked immunoabsorbent assay (ELISA) to measure the binding ability of the peptide analog synthesized in Example 1 to polo-like phosphorylase-1-derived poloxane domain. The biotin-labeled p-T78 (DPPLHSpTAIYADEE-NH2) peptide was diluted to 0.3 [mu] M and immobilized on a 96-well plate coated with streptavidin. Thereafter, the cells were washed with PBS (containing 0.05% Tween 20 in Phosphate Buffer Saline), and then blocked with 1% BSA. A mitochondrial 293A cell lysate expressing HA-EGFP-Plk1 was added to the plate on which the peptide was immobilized, and then the peptide to be assayed for inhibitory activity was added thereto. Then, after washing with PBS, HA-EGFP-PLK1 immobilized on the plate was added to 100 μL per well, followed by washing to add secondary antibody immobilized with alkaline phosphatase. Thereafter, 100 μL / well of 3,3 ', 5,5'-tetramethylbenzimidine (TMB) solution was added and the reaction was quenched with 1 N sulfuric acid. Thereafter, the absorbance at 450 nm was measured. The results are shown in FIG. 2. Here, the concentration at which 50% inhibition of binding of HA-EGFP-PLK1 to p-T78 peptide is defined as IC50, 1 and AB103-5, AB103-6, AB103-8 and AB103-9 inhibited the binding of polo-like phosphorylase-1 to the original binding protein with an IC50 of 0.01 mM or less.

< Example  3>

Peptides  Cytotoxicity measurement of analogue

To measure the cytotoxicity of the peptide analog synthesized in Example 1, the present inventors purchased a human cancer cell line HeLa (human epithelial carcinoma cell line) cell line from ATCC (American Type Culture Collection) Respectively. In the case of AB103-5, AB103-5-Cys, AB103-5-PEG, AB103-8, AB103-8-Cys and AB103-8-PEG, peptides were synthesized in the same manner as in Example 1, Of cysteine was added to the N-terminus. PEG was then introduced by adding PEG activated with maleimide.

HeLa cells at 1 × 10 ³ cells per well were seeded in 96-well plates containing Dubelco's Modified Eagle Medium (DMEM, GIFCO BRL, Gaithersburg, MD, USA) and 10% fetal bovine serum (FBS) After culturing, the peptide analogs (AB103-5, AB103-5-Cys, AB103-5-PEG, AB103-8, AB103-8-Cys at a concentration of 1, 10, 30, 50, 80, 100, Cys and AB103-8-PEG) were treated and cultured for 24 hours. The cytotoxicity of the peptide analogues was measured by Cell Proliferation Reagent, sodium 3- [1- (phenylaminocarbonyl) -d, 4-tetrazolium] -bis (4-methoxy-6-nitro) benzene sulfonic hydrate (XTT, Sigma-Aldrich, USA) Observations were made through the measurements, and the experiment was carried out over three replicates.

As a result of the observation, it was confirmed that AB103-8-PEG and AB103-5-PEG, which are compounds that bind PEG to AB103-5 and AB103-8, permeate the cell membrane and show cytotoxicity.

< Example  4>

Peptides  Measure cancer cell permeability of analogue

The present inventors used a technique of introducing fluorescein 5 (6) -isothiocyanate (FITC) into peptide analogs (AB103-5-PEG and AB103-8-PEG) to measure the membrane permeability of peptide analogs in cancer cell lines. HeLa cells of 2 x 10 ⁴ cells per well were covered with a 24-well polystyrene plate for 24 hours. The medium was then replaced with 200 μM peptide analog and FBS free DMEM and incubated for 3 hours. The covers were washed 3 times in phosphate-buffered saline (PBS) solution. The cover was fixed with a mount solution (VECTOR Shield.VECTOR corp., USA) and images were output to a fluorescence microscope (OLYMPUS IX81, Olympus Inc, Japan). Images were processed using image analysis software (Metamorph, Molecular Devices Inc., USA).

The results are shown in FIG. 4, confirming that PEG-linked peptide analogs can penetrate into the cancer cell membrane.

< Example  5>

Peptides  Analogous Polo-like phosphorylase -1 inhibition activity measurement

The present inventors measured the inhibitory activity of polo-like phosphorylase-1 to confirm the anticancer activity of the peptide analogue.

First, CycLex? Cancer cells (2.5 × 10 ⁵ cells / well) were cultured on a 6-well plate for 24 hours, and 200 μM of a peptide analogue (AB103- 5, AB103-5-PEG, AB103-8 and AB103-8-PEG) and medium were added and cultured for 12 hours. The total protein purified from the cancer cells was then extracted with 300 μM extraction buffer (20 mM, Tris-HCL, pH 8.5, 150 mM NaCl, 0.2% NP-40, 1 mM DTT, 1 mM EDTA, 1 mM EGTA, 0.2 mM, and 5 mM β -mercaptoethanol). &lt; / RTI &gt; Samples (30 μg / 100 μl of protein and phosphorylation reaction buffer) were incubated at 30 ° C. for 30 minutes. After washing 5 times in the wash buffer, the cells were incubated in 100 μL of anti-phospho-serine / threonine polyclonal antibody PPT-07 solution for 60 min at room temperature and cultured in 100 μL of HRP-conjugated anti-rabbit IgG for 60 min at room temperature. And incubated in 100 μL of substrate reaction solution for 10 minutes at room temperature. Finally, 100 μL of stop solution was added to each well and the same amount of substrate reaction was added. The absorbance of each well was measured using a spectrophotometric plate reader at 450 nm / 560 nm.

As a result of the measurement, it was confirmed that the peptide mutant into which PEG was introduced successfully penetrated the cell membrane and inhibited the activity of polo-like phosphorylase-1 (FIG. 5). Thus, using the peptide analog synthesized in the present invention, Can be prepared.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

<110> Chungbuk National University Industry-Academic Cooperation Foundation <120> Peptide analog binding to polo-box domain of polo-like kinase-1          and pharmaceutical compositions for anti-cancer containing, <130> PN1409-272 <160> 2 <170> Kopatentin 2.0 <210> 1 <211> 603 <212> PRT <213> Mus musculus <400> 1 Met Asn Ala Ala Ala Lys Ala Gly Lys Leu Ala Arg Ala Pro Ala Asp   1 5 10 15 Leu Gly Lys Gly Gly Val Pro Gly Asp Ala Val Pro Gly Ala Pro Val              20 25 30 Ala Ala Pro Leu Ala Lys Glu Ile Pro Glu Val Leu Val Asp Pro Arg          35 40 45 Ser Arg Arg Gln Tyr Val Arg Gly Arg Phe Leu Gly Lys Gly Gly Phe      50 55 60 Ala Lys Cys Phe Glu Ile Ser Asp Ala Asp Thr Lys Glu Val Phe Ala  65 70 75 80 Gly Lys Ile Val Pro Lys Ser Leu Leu Leu Lys Pro His Gln Lys Glu                  85 90 95 Lys Met Ser Met Glu Ile Ser Ile His Arg Ser Leu Ala His Gln His             100 105 110 Val Val Gly Phe His Asp Phe Phe Glu Asp Ser Asp Phe Val Phe Val         115 120 125 Val Leu Glu Leu Cys Arg Arg Arg Ser Leu Leu Glu Leu His Lys Arg     130 135 140 Arg Lys Ala Leu Thr Glu Pro Glu Ala Arg Tyr Tyr Leu Arg Gln Ile 145 150 155 160 Val Leu Gly Cys Gln Tyr Leu His Arg Asn Gln Val Ile His Arg Asp                 165 170 175 Leu Lys Leu Gly Asn Leu Phe Leu Asn Glu Asp Leu Glu Val Lys Ile             180 185 190 Gly Asp Phe Gly Leu Ala Thr Lys Val Glu Tyr Glu Gly Glu Arg Lys         195 200 205 Lys Thr Leu Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Val Leu Ser     210 215 220 Lys Lys Gly His Ser Phe Glu Val Asp Val Trp Ser Ile Gly Cys Ile 225 230 235 240 Met Tyr Thr Leu Leu Val Gly Lys Pro Pro Phe Glu Thr Ser Cys Leu                 245 250 255 Lys Glu Thr Tyr Leu Arg Ile Lys Lys Asn Glu Tyr Ser Ile Pro Lys             260 265 270 His Ile Asn Pro Val Ala Ala Ser Leu Ile Gln Lys Met Leu Gln Thr         275 280 285 Asp Pro Thr Ala Arg Pro Thr Ile His Glu Leu Leu Asn Asp Glu Phe     290 295 300 Phe Thr Ser Gly Tyr Ile Pro Ala Arg Leu Pro Ile Thr Cys Leu Thr 305 310 315 320 Ile Pro Pro Arg Phe Ser Ile Ala Pro Ser Ser Leu Asp Pro Ser Ser                 325 330 335 Arg Lys Pro Leu Lys Val Leu Asn Lys Gly Val Glu Asn Pro Leu Pro             340 345 350 Asp Arg Pro Arg Glu Lys Glu Glu Pro Val Val Arg Glu Thr Asn Glu         355 360 365 Ala Ile Glu Cys His Leu Ser Asp Leu Leu Gln Gln Leu Thr Ser Val     370 375 380 Asn Ala Ser Lys Pro Ser Glu Arg Gly Leu Val Arg Gln Glu Glu Ala 385 390 395 400 Glu Asp Pro Ala Cys Ile Pro Ile Phe Trp Val Ser Lys Trp Val Asp                 405 410 415 Tyr Ser Asp Lys Tyr Gly Leu Gly Tyr Gln Leu Cys Asp Asn Ser Val             420 425 430 Gly Val Leu Phe Asn Asp Ser Thr Arg Leu Ile Leu Tyr Asn Asp Gly         435 440 445 Asp Ser Leu Gln Tyr Ile Glu Arg Asp Gly Thr Glu Ser Tyr Leu Thr     450 455 460 Val Ser Ser His Pro Asn Ser Leu Met Lys Lys Ile Thr Leu Leu Asn 465 470 475 480 Tyr Phe Arg Asn Tyr Met Ser Glu His Leu Leu Lys Ala Gly Ala Asn                 485 490 495 Ile Thr Pro Arg Glu Gly Asp Glu Leu Ala Arg Leu Pro Tyr Leu Arg             500 505 510 Thr Trp Phe Arg Thr Arg Ser Ale Ile Ile Leu His Leu Ser Asn Gly         515 520 525 Thr Val Gln Ile Asn Phe Phe Gln Asp His Thr Lys Leu Ile Leu Cys     530 535 540 Pro Leu Met Ala Ala Val Thr Tyr Ile Asn Glu Lys Arg Asp Phe Gln 545 550 555 560 Thr Tyr Arg Leu Ser Leu Leu Glu Glu Tyr Gly Cys Cys Lys Glu Leu                 565 570 575 Ala Ser Arg Leu Arg Tyr Ala Arg Thr Met Val Asp Lys Leu Leu Ser             580 585 590 Ser Arg Ser Ala Ser Asn Arg Leu Lys Ala Ser         595 600 <210> 2 <211> 1812 <212> RNA <213> Homo sapiens <400> 2 atgagtgctg cagtgactgc agggaagctg gcacgggcac cggccgaccc tgggaaagcc 60 ggggtccccg gagttgcagc tcccggagct ccggcggcgg ctccaccggc gaaagagatc 120 ccggaggtcc tagtggaccc acgcagccgg cggcgctatg tgcggggccg ctttttgggc 180 aagggcggct ttgccaagtg cttcgagatc tcggacgcgg acaccaagga ggtgttcgcg 240 ggcaagattg tgcctaagtc tctgctgctc aagccgcacc agagggagaa gatgtccatg 300 cggctttttc gaggacaacg acttcgtgtt cgtggtgttg gagctctgcc gccggaggtc tctcctggag 420 ctgcacaaga ggaggaaagc cctgactgag cctgaggccc gatactacct acggcaaatt 480 gtgcttggct gccagtacct gcaccgaaac cgagttattc atcgagacct caagctgggc 540 aaccttttcc tgaatgaaga tctggaggtg aaaatagggg attttggact ggcaaccaaa 600 gtcgaatatg acgggagag gaagaagacc ctgtgtggga ctcctaatta catagctccc 660 gaggtgctg gcaagaaagg gcacagtttc gaggtggatg tgtggtccat tgggtgtatc 720 atgtatacct tgttagtggg caaaccacct tttgagactt cttgcctaaa agagacctac 780 ctccggatca agaagaatga atacagtatt cccaagcaca tcaaccccgt ggccgcctcc 840 ctcatccaga agatgcttca gacagatccc actgcccgcc caaccattaa cgagctgctt 900 aatgacgagt tctttacttc tggctatatc cctgcccgtc tccccatcac ctgcctgacc 960 attccaccaa ggttttcgat tgctcccagc agcctggacc ccagcaaccg gaagcccctc 1020 acagtcctca ataaaggctt ggagaacccc ctgcctgagc gtccccggga aaaagaagaa 1080 ccagtggttc gagagacagg tgaggtggtc gactgccacc tcagtgacat gctgcagcag 1140 ctgcacagtg tcaatgcctc caagccctcg gagcgtgggc tggtcaggca agaggaggct 1200 gaggatcctg cctgcatccc catcttctgg gtcagcaagt gggtggacta ttcggacaag 1260 tacggccttg ggtatcagct ctgtgataac agcgtggggg tgctcttcaa tgactcaaca 1320 cgcctcatcc tctacaatga tggtgacagc ctgcagtaca tagagcgtga cggcactgag 1380 tcctacctca ccgtgagttc ccatcccaac tccttgatga agaagatcac cctccttaaa 1440 tatttccgca attacatgag cgagcacttg ctgaaggcag gtgccaacat cacgccgcgc 1500 gaaggtgatg agctcgcccg gctgccctac ctacggacct ggttccgcac ccgcagcgcc 1560 atcatcctgc acctcagcaa cggcagcgtg cagatcaact tcttccagga tcacaccaag 1620 ctcatcttgt gcccactgat ggcagccgtg acctacatcg acgagaagcg ggacttccgc 1680 acataccgcc tgagtctcct ggaggagtac ggctgctgca aggagctggc cagccggctc 1740 cgctacgccc gcactatggt ggacaagctg ctgagctcac gctcggccag caaccgtctc 1800 aaggcctcct aa 1812

Claims (8)

A novel peptide analogue having the structure of formula (1), or a stereoisomer or pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,

And all of the carboxyl acid derivatives having an aromatic ring at the N-terminus. An anticancer composition comprising the novel peptide analogue of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, as an active ingredient. 3. The method of claim 2,
Wherein the novel peptide analogue, or a stereoisomer or pharmaceutically acceptable salt thereof, has high affinity and selectively binds to the poloxane domain of polo-like phosphorylase-1. The method of claim 3,
Wherein said binding binds to the phosphorylated peptide binding site of the poloxane domain of polo-like phosphorylase-1. 5. The method of claim 4,
Wherein the polo box domain of polo-like phosphorylase-1 comprises the amino acid sequence of SEQ ID NO: 1. 5. The method of claim 4,
The phosphorylated peptide binding site comprises the 414th tryptophan, the 415th valine, the 416th aspartic acid, the 417th tyrosine, the 481st tyrosine and the 485th tyrosine in the pololoxane domain protein of polo-like phosphorylase-1 comprising the amino acid sequence of SEQ ID NO: &Lt; / RTI &gt; 3. The method of claim 2,
Wherein the anticancer composition comprises a novel peptide analogue of Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a concentration of 1 to 500 μM. 3. The method of claim 2,
Wherein the anticancer composition inhibits the activity of polo-like kinase-1 (PLK-1 kinase).

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