JP2017218382A - Parp inhibitor containing syzygium samarangense extract - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a poly ADP ribose polymerase (PARP) inhibitor and a BRCA1/2 gene mutation positive advanced ovarian cancer therapeutic drug by using a novel PARP inhibitory substance obtained from spontaneous plants as a source.SOLUTION: The present invention is a poly ADP ribose polymerase (PARP) inhibitor containing extract derived from syzygium samarangense leaves, a poly ADP ribose polymerase (PARP) inhibitor having at least one or more of Castalagin and Vescalagin as active ingredient, and a BRCA1/2 gene mutation positive advanced ovarian cancer therapeutic drug having the inhibitor as an active ingredient.SELECTED DRAWING: Figure 2

Description

The present invention relates to a poly ADP ribose polymerase (PARP) inhibitor comprising a ream (Syzygium samarangense) extract.

In the poly (ADP-ribose) polymerase (PARP) family, PARP1 and PARP2 are activated by binding to DNA cleavage sites and are responsible for polyADP ribosylation (PARylation). .
These PARPs are thought to be closely related to the performance of DNA repair through their responses. In December 2014, the PARP inhibitor Olaparib was developed as a germline BRCA1 / 2 mutation. Approved by the US FDA for the treatment of positive advanced ovarian cancer.
In January 2016, the FDA proposed olaparib as a breakthrough treatment for certain types of patients with genetically-mutated prostate cancer.
In particular, PARP1 is required along with other repair-related factors in both the process of single-strand break (SSB) repair by base excision repair and double-strand break repair by homologous recombination (HR). Is a factor.
BRCA1 / 2 is also involved in the repair process of double-strand breaks. For cancers with mutations in these genes, the combination of anticancer drugs that induce DNA damage and PARP inhibitors provides high therapeutic effects In recent years, PARP1 has attracted attention as a therapeutic target for BRCA1 / 2 gene mutation-positive ovarian cancer (Non-patent Document 1).
However, olaparib has been reported to cause 54% of serious adverse events of Grade 3 or higher, such as anemia, fatigue, nausea that affects the heart, and vomiting.
In addition, if a mutation occurs in the BRCA1 and BRCA2 genes that encode two important proteins to repair damaged DNA inside the cell, the BRCA gene may develop cancer in the breast and ovary (for breast cancer). It is said that the risk is 87% and the risk of ovarian cancer is 50%.), And the risk of cancer recurrence within 10 years from the first diagnosis is increased.
Therefore, the development of PARP inhibitors with high side effects and low effects has been demanded.

On the other hand, the yellow peach is an evergreen tree native to Southeast Asia cultivated in a subtropical or tropical climate.
Ofo tomo, the fruit is mainly used as raw food, has a unique look and acidity, and tastes like an apple.
In addition, the white leaves are oval with a length of about 20 cm, but there are no special applications.

Andreina Peralta-Lear et al .: PARP inhibitors: New partners in the therapy of cancer and inflammatory diseases, Free Radical Biology & Medicine 47,13-26,2009

The inventors have been studying the effective utilization of Okinawa's native plants for many years, and have been working on providing useful components that enable PARP inhibition using Okinawa's native plants.

The inventors found a plant containing a useful component having PARP inhibitory activity from among approximately 160 kinds of Okinawan native plants, and clarified the characteristics of the PARP inhibitory compound contained in the useful component. , Completed the invention.

The present invention has the following configuration.
The 1st structure of this invention is a PARP inhibitor characterized by including the leaf extract of a yellow peach.
A second configuration of the present invention is the PARP inhibitor according to the first configuration, wherein the extract has five gallic acids and a ring-opened hexose structural unit.
A third configuration of the present invention is the PARP inhibitor according to the first configuration, wherein the extract has C-glycoside type ellagitannin.
A fourth configuration of the present invention is the PARP inhibitor according to the first configuration, wherein the extract is composed of one or more of Castalagin and Vescalagin.
A fifth configuration of the present invention is a therapeutic agent for BRCA1 / 2 gene mutation-positive advanced ovarian cancer characterized by comprising the PARP inhibitor described in the first to fourth configurations as an active ingredient.

The characteristics of the poly ADP ribose polymerase inhibitor of the present invention are milder than those of chemically synthesized drugs, and because it is a component identified from Rembu, a native plant that has been popular as a food resource for many years in Okinawa, it has side effects. High safety including
According to the present invention, a useful and safe PARP inhibitor can be provided in order to cure a patient suffering from BRCA1 / 2 mutant breast cancer or ovarian cancer as soon as possible.
That is, the component extracted from the leaves of the leaves of the present invention enables PARP inhibition, and can also be expected as a therapeutic agent for BRCA1 / 2 gene mutation-positive advanced ovarian cancer from its mechanism.

Diagram showing how to extract and preserve useful components from Okinawa native plants Diagram showing experimental and analytical methods of screening assay for examining PARP inhibitory activity Figure excerpting the results of a comparative study of the PARP inhibitory activity of 162 types of leaf or fruit extract The figure which showed the extraction method of the useful component from the yellow peach leaf and the purification method of the fraction (Castalagin: AQ2) which shows PARP inhibitory activity The figure which showed the extraction method of the useful component from the yellow peach leaf and the purification method of the fraction (Vescalagin: AQ1) which shows PARP inhibitory activity AQ2 ESI-MS analysis results Diagram showing ESI-MS analysis results for AQ1 and AQ2 (upper: AQ2, lower: AQ1) The figure which showed the NMR analysis result of AQ2 Figure showing the NMR analysis results of AQ2 that was pretreated for methylation Diagram showing the estimated structure of AQ1 and AQ2 Figure showing the results of examining the effects of acid or alkali treatment on PARP inhibitory activity of AQ2 Flow chart showing the analysis procedure of poly ADP ribosylation product (poly ADP ribosylation protein; PAR protein) Left figure: Analysis of AQ1 and AQ2 IC ₅₀ for PARP activity, right figure: Confirmation of inhibition of PAR protein formation by AQ1 and AQ2 according to the procedure of [Figure 11] Diagram of IC ₅₀ values of olaparib, an existing PARP inhibitor The figure which showed the experimental result which compared AQ2 and the PARP inhibitory activity of the existing PARP inhibitor The figure which showed the experimental result which examined the inhibitory effect of AQ1 and AQ2 on the poly ADP ribosylation reaction of cultured cells (SH-SY5Y) under physiological conditions The figure which showed the experimental result which examined the inhibitory effect of AQ1 and AQ2 on the poly ADP ribosylation reaction of the cell (U937) which caused DNA damage by UV irradiation The figure which showed the experimental result which examined whether the pretreatment of AQ2 caused the inhibitory action of PARP The figure which showed the experimental result which examined the Zn ²⁺ chelate effect of AQ2 using alkaline phosphatase (ALP) The figure which showed the experimental result which examined restriction effect of Mg ²⁺ chelate effect of AQ1 and AQ2

  The PARP inhibitor of the present invention will be described.

  The PARP inhibitor of the present invention is based on the discovery that the component of PARP inhibitor is included in the leaves of fruit and fruits of 162 kinds of Okinawa native plants, and the leaf of white peach contains PARP inhibition. It is.

Extraction of useful components from the black peach is not particularly limited as long as useful components can be extracted, and various extraction methods can be used.
One example is the extraction of organic peach leaves or raw material samples that have been pretreated such as drying.
The organic solvent in this case is not particularly limited, and various organic solvents can be used, and typically ethanol can be used.
The organic solvent containing the active ingredient after extraction should be stored in liquid form or as a solid by freeze-drying, etc., if necessary, after removing impurities by centrifugation, concentrating, and separating the liquid. (Hereafter referred to as “active ingredient sample”).

When using the active ingredient sample, it is desirable to include a fraction having 5 gallic acids and a ring-opened hexose structural unit.
That is, an active ingredient showing PARP inhibition (hereinafter referred to as “PARP inhibitor compound”) contained in the active ingredient has the following structural characteristics in terms of analysis by MS or NMR.
(1) A compound with 41 carbon atoms, 26 or more oxygen atoms, and a molecular weight of 934 and has 15 acidic hydroxyl groups.
(2) When NMR analysis is performed, 6 signals are observed at δ60-80 and no signal is observed at δ90-100.
(3) Upon NMR analysis, 35 signals were observed at δ105-175, of which 5 were δ165-175 carbonyl regions.

From these facts, it is highly presumed that PARP-inhibiting compounds have five gallic acids and a ring-opened hexose structural unit.
However, the PARP inhibitor compound is not necessarily limited to this.
That is, the above-mentioned features (1) to (3) are only one of the PARP inhibitor compounds contained in the active ingredient samples confirmed in the experimental examples in the present application, and include different structures as structures. This is because it leaves room.

With regard to the active ingredient sample, the PARP inhibitor compound can be purified from the active ingredient sample and used, or the active ingredient sample may be used as it is as a PARP inhibitor.
The purification of the PARP inhibitor compound from the active ingredient sample is not particularly limited as long as the PARP inhibitor compound can be purified, and various purification methods can be used.
Typically, a fraction containing a PARP inhibitor compound is collected by HPLC, and this is subjected to further purification by evaporating or desalting an organic solvent as necessary.

  Regarding PARP inhibitor compounds, Castalagin and Vescalagin can be used as specific compounds, and PARP inhibitor compounds containing any one or more of these compounds, or BRCA1 / 2 gene mutation-positive advanced ovarian cancer treatment drugs can be configured. it can.

In the present invention, a therapeutic agent for BRCA1 / 2 gene mutation-positive advanced ovarian cancer refers to a BRCA1 / 2 gene mutation-positive advanced ovarian cancer that exhibits a PARP inhibitory effect in vivo by a PARP inhibitor compound such as Castalagin or Vescalagin. Defined as a drug that exhibits a therapeutic effect.
For such drugs, in addition to the case where the PARP inhibitor compound itself functions as an active ingredient, in view of the gist of the present invention, a so-called DDS in which the PARP inhibitor compound functions as an active ingredient by changing the molecular form in vivo after administration in view of the spirit of the present invention It is also included if In addition, these PARP-inhibiting compounds can be extracted and purified from the yellow peach leaf as a raw material, but in view of the gist of the present invention, the chemical structure is clarified and not an extract from the yellow peach leaf, Chemically synthesized products may be used.

  The dosage form of the therapeutic agent for BRCA1 / 2 gene mutation-positive advanced ovarian cancer of the present invention is not particularly limited, and various forms such as oral preparations, tablets, capsules, powders, transdermal preparations can be adopted. it can. Preferably, oral preparations are used, and as shown in Experimental Example 3 (FIG. 11), AQ1 and AQ2 which are examples of the active ingredient of the present invention are stable against acids, so that they are easy to handle and compliance. From this point of view, it is preferable to configure as an oral preparation.

  Hereinafter, the PARP inhibitor in the present invention will be described using experimental examples.

<< Experimental example 1, screening from Okinawa native plants >>
1. 162 kinds of Okinawa native plants were used for the purpose of finding components having PARP inhibitory activity from the leaves and fruits.
2. Fig. 1 shows a method for extracting useful components from leaves and fruits, and Fig. 2 shows a method for assaying PARP inhibitory activity.

3. Assay method for PAR synthesis
PAR synthesis reaction solution (10 μM NAD ⁺ , 15 μg / ml nicked DNA, 50 mM Tris-HCl buffer pH 8.0, 10 mM MgCl ₂ , 0.25 μg PARP1) is reacted at 25 ° C. for 30 minutes, and 2M KOH, 20% acetophenone (50 μl) is added Then, after cooling in a dark room at 4 ° C for 10 minutes, 88% formic acid (225 µl) was added and heat-treated at 110 ° C for 5 minutes to make the residual NAD ⁺ a fluorescent derivative, and the fluorescence intensity was measured.
4). Definition of PARP inhibitory activity PARP inhibitory activity was determined using the above PAR synthesis reaction system.
As PAR synthesis proceeds, NAD ⁺ is consumed and fluorescence intensity decreases.
If a PARP inhibitor is added, PARP activity is suppressed, consumption of NAD ⁺ is suppressed, and as a result, fluorescence intensity increases.
Therefore, the difference in the fluorescence intensity after the reaction of both the PARP non-added and the added reaction system is obtained, and the difference is defined as PARP activity 100% (temporarily A).
On the other hand, B is the difference between the fluorescence intensity after reaction in the presence of PARP and a PARP inhibitor and the fluorescence intensity after reaction in the presence of PARP.
For convenience, the PARP inhibitory activity was B / A × 100 (FIG. 2).

5). FIG. 3 shows a part of the results of the PARP inhibition assay.
Through these series of experiments, three kinds of extracted components (No. 63, No. 67, No. 103) showing relatively high PARP inhibitory activity were found, and one of them (No. 63 in FIG. 3) Since then, experiments have been carried out on the leaves of the yellow peach.

<< Experimental example 2, structural analysis of the leaf extract of the yellow peach >>
1. 4 and 5 show a method for extracting a component from a yellow peach leaf and a method for purifying an active component.
By this purification method, two components (AQ1, AQ2) were obtained as fractions having PARP inhibitory activity.
The two components (AQ1, AQ2) were analyzed by Mass and NMR, and experiments were conducted to clarify their structures.
As a result, AQ1 and AQ2 were estimated to be Vescalagin and Castalagin, respectively, but AQ1 and AQ2 were isolated as follows (hereinafter “Castalagin” was AQ2, “Vescalagin” was AQ1). means.).
(1) Castalagin leaves are also collected from a private house in Okinawa City in 2014, dried at 60 ° C, and then ground (IKA MF10, 3000rpm cutter mill φ1mm sieve) did.
Extraction is performed using a high-speed solvent extraction system (DIONEX ASE-350), 90 g of the extraction sample (sample / Celite 45:45) is filled in 45 g into two 100 mL cells, water is used as the solvent, 85 ℃, 1500 psi, standing time 10 minutes, flush capacity 60%, purge time 300 seconds.
The resulting aqueous extract (250 mL) was returned to room temperature and then roughly separated on a column (φ50mm × L100mm) packed with ODS (YMC YMC-Pack ODS-AQ 120-S50) (solvent system: 0.1% formic acid → 0.1% formic acid / acetonitrile 80:20, flow rate 27 mL / min).
The obtained castalagin-containing fraction (426 mg) was separated by gel filtration (Tosoh Corporation TOYOPEARL HW40F, φ30 mm × L300 mm) (water / acetonitrile 75:25, flow rate 6 mL / min) to obtain crude castalagin (153 mg).
This crude castalagin was finally purified by countercurrent chromatography (Mikisha CPC-LLB-M) (1100 rpm, water / n-butanol / n-propanol 100: 45: 55, upper mobile phase, flow rate 2.5 mL / min. 106 mg of castalagin was obtained as a light brown amorphous.
(2) The leaves of Vescalagin's isolated remnants (aka: Ototomomo) were collected from a private house in Okinawa City in 2014, dried at 60 ° C, and then crushed (IKA MF10, 3000rpm cutter mill φ1mm sieve) .
70 g of sample was extracted with 700 mL of acetone / water 7: 3 (left for 1 day) and then solid-liquid separated by centrifugation (3000 rpm, 30 minutes).
The solid was extracted twice more with 700 mL of acetone / water 7: 3 (1 day standing), and then solid-liquid separation was performed by centrifugation (3000 rpm, 30 minutes).
A total of about 2000 mL of extract was obtained by three extraction operations.
The extract was filtered (Toyo Roshi Kaisha GA-100), then acetone was removed under reduced pressure and further concentrated to obtain about 500 mL of an aqueous extract.
This was separated with 500 mL of ethyl acetate, and the lower phase (aqueous phase) was subjected to removal of ethyl acetate under reduced pressure and further concentrated to obtain about 250 mL of an extract.
The extract was roughly separated (0.1% formic acid → 0.1% formic acid / acetonitrile 80:20, flow rate 27 mL / min) on a column (φ50mm × L100mm) packed with ODS (YMC YMC-Pack ODS-AQ 120-S50). went.
The obtained fraction containing vescalagin (463 mg) was separated by gel filtration (Tosoh Corporation TOYOPEARL HW40F, φ30 mm × L300 mm) (water / acetonitrile 75:25, flow rate 6 mL / min) to obtain crude vescalagin (236 mg).
This crude vescalagin was finally purified by gel filtration (Tosoh Corporation TOYOPEARL HW40F, φ30 mm × L300 mm) (water / acetonitrile 75:25, flow rate 2.5 mL / min) to obtain 205 mg of vescalagin as a light brown amorphous.

2. Fig. 6 shows the ESI-MS analysis results for AQ2, and Fig. 7 shows the ESI-MS analysis results for AQ1 and AQ2 (upper: AQ2, lower: AQ1).
From these analysis results, the molecular weight of both AQ1 and AQ2 is considered to be 934.

3. FIG. 8 shows the NMR analysis results of AQ2.
Since 6 signals at δ60-80 and no signal at δ90-100 are not observed, AQ2 is considered to have a ring-opened hexose structure (Fig. 8, bottom).
Since 35 signals were observed at δ105-175, of which 5 were carbonyl regions of δ165-175, AQ2 is considered to have 5 structural units of gallic acid (Fig. 8, bottom).
Since it has 41 carbon atoms, 26 or more oxygen atoms, and a molecular weight of 934, the molecular formula of AQ2 is estimated to be C ₄₁ H ₂₆ O ₂₆ .

4). FIG. 9 shows the NMR analysis results of the AQ2 methylated compound.
From the analytical results of NMR by diazomethane treatment that methylates the hydroxyl group, AQ2 is estimated to have 15 acidic hydroxyl groups (phenolic or carboxylic acid) (FIG. 9, top).

These results suggest that AQ2 is castalagin or vescalagin.
In addition, AQ1 is highly likely to be vescalagin or castalagin, which has an isomer relationship with AQ2, since the MS spectrum is almost identical to that of AQ2.

Therefore, in order to confirm this, based on NMR spectral data of AQ2 (Table 1), specific rotation ([α] ²⁴ _D = −94.5 °) and UV spectral data (UV λ 224 nm 285 nm (Sh)). It matched when compared with that of castalagin.

Therefore, AQ2 was identified as castalagin (FIG. 10).
As with AQ2, AQ1 was consistent with that of vescalagin, an isomer of castalagin, based on NMR spectral data, specific rotation, and UV spectral data.
Therefore, AQ1 was identified as vescalagin (FIG. 10).
Both vescalagin and castalagin are C-glycoside ellagitannins.

<< Experimental Example 3, AQ2 PARP Inhibition Assay >>
1. An experiment was conducted with the aim of examining the potential of AQ2 as an oral drug by knowing its structural stability.
The table briefly shows each preprocessing method.

2. FIG. 11 shows the results of PARP inhibition assay after pretreatment of AQ2.
(1) It was found that AQ2 was stable to acid even when pretreated with acid, and PARP inhibitory activity was almost the same as that of neutral treatment.
(2) On the other hand, in the case of alkali treatment, the activity is remarkably reduced, and it is considered that the structure of AQ2 itself has changed due to alkali treatment, and it is unstable to alkali. I understood.
3. These results suggest that AQ2 can be designed as an oral drug because it is stable at least against acids.

<< Experimental Example 4, Comparison of PARP inhibitory ability between AQ2 and existing compounds >>
1. An experiment was conducted with the aim of confirming the degree of PARP inhibitory ability of AQ2 compared to existing PARP inhibitors.

2. An outline of a method for examining PARP inhibition other than the PARP activity inhibition assay method shown in FIG. 2 is shown in FIG. This method is a method for immunochemically measuring a PAR protein, which is a product of poly ADP ribosyl (PAR) reaction.
3. Based on the measurement method of PARP inhibitory activity in FIG. 2, the inhibitory activity of AQ1 and AQ2 was examined, and the IC ₅₀ value of AQ2 and olaparib, which is an existing PARP inhibitor, was calculated.
(1) Both AQ1 and AQ2 showed the same inhibitory activity, and the IC ₅₀ value was 0.8 μg / mL (856 nM) (FIG. 13, left).
(2) On the other hand, the IC ₅₀ value of olaparib was calculated in the same experimental system and found to be approximately 15 nM (FIG. 14).
(3) Although it has been described that gallic acid is highly likely to be a structural unit of AQ1 and AQ2, this gallic acid was also examined and showed no PARP inhibitory activity even at 10 μM (FIG. 14). .

4). FIG. 15 shows the results of the PARP inhibition assay using AQ2, olaparib, 3-aminobenzamide, gallic acid, and these compounds.
(1) AQ2 was lower than olaparib and had an inhibitory capacity exceeding that of 3-aminobenzamide.
(2) In addition, gallic acid did not show PARP inhibitory activity as in the above-mentioned result (FIG. 14).

<< Experimental Example 5, Confirmation of PARP Inhibitory Activity by AQ1 and AQ2 Using Neuroblastoma Cells SH-SY5Y >>
1. An experiment was conducted to investigate how PAR synthesis changes when PARP inhibition by AQ1 and AQ2 is performed using the neuroblastoma cell SH-SY5Y.

2. SH-SY5Y cells were cultured overnight in DMEM + 10% FCS medium supplemented with AQ1 and AQ2, and soluble proteins were prepared from the collected cells and used as samples for SDS-PAGE (SDS polyacrylamide gel electrophoresis).
After electrophoresis, the protein was transferred to a PVDF membrane, and the PAR chain covalently bound to the protein was detected using an anti-poly ADP ribose antibody as the primary antibody.
Olaparib was used as a positive control for PARP inhibitors.

3. FIG. 16 shows the result.
(1) Compared to the band shown on the leftmost dark ladder, which is the control, the band due to pretreatment with AQ1 and AQ2 at a concentration of 3 μg / mL was thinner, which inhibited PAR synthesis. I found out.
(2) Compared with the 3μg / mL concentration, the 15μg / mL concentration of AQ1 and AQ2 bands became deeper, indicating that the PARP inhibitory effect was suppressed. The cause of this is unknown.
(3) In 10 μM olaparib, PAR synthesis was strongly inhibited.

<< Experimental Example 6, AQ Inhibitory Effect on Damaged DNA-Dependent PAR Synthesis >>
1. Experiments were conducted with the aim of elucidating the effects of AQ1 etc. on PAR synthesis induced by DNA damage caused by UV irradiation.

2. U937 cells were cultured in RPMI1640 + 10% FCS medium supplemented with AQ, etc. for 2 hours, and irradiated with ultraviolet rays (10 mJ total amount / cm ² ).
After 2 hours of recovery time, soluble protein was prepared from the collected cells, and protein-bound PAR chains were detected according to the method of Experimental Example 5.

3. FIG. 17 shows the result.
(1) Compared with the second band from the left, which is a control of DNA damage, PAR synthesis was not suppressed by treatment with AQ1 and AQ2.
(2) On the other hand, olaparib strongly suppressed PAR synthesis.

<< Experimental Example 7, A Study on AQ2 PARP Inhibition Mechanism >>
1. An experiment was conducted to clarify the mechanism by which AQ2 inhibits PARP.

2. FIG. 18 shows the results of examining the inhibitory activity by AQ2 after pretreatment of PARP with AQ2.
(1) The inhibitory activity of AQ2 was almost unchanged even when the inhibitory activity of AQ2 was compared in the presence or absence of pretreatment with AQ2 previously reacted with PARP.
(2) In addition, the concentration-dependent inhibitory activity effect of AQ2 was not changed in all cases.
(3) From these results, it was considered that there is no possibility that AQ2 exerts an inhibitory activity effect due to structural changes such as irreversible binding to the PARP molecule itself.

3. FIG. 19 shows the results of studies on the Zn chelating ability of AQ2.
In other words, since PARP is an enzyme that requires Zn (Zn enzyme), the possibility that AQ2 captures Zn with a chelate and reduces PARP activity is an alkaline phosphatase that is an enzyme that requires Zn. (ALP) has been studied.
(1) Compared with DMSO, which was a negative target, ALP activity due to the addition of AQ2 hardly changed, and even when the concentration was changed, no effect was seen.
(2) It was found that ALP activity did not change even when olaparib was added.
(3) From these results, it is considered that AQ2 may not exhibit the PARP inhibitory effect by chelating Zn.

4). FIG. 20 shows the results of examining whether AQ1 or the like has an inhibitory effect on the excision of inserts by two types of restriction enzymes NheI and XhoI using pcDNA3 / HA-DNp73α as a substrate.
That is, PARP requires about 10 mM Mg ²⁺ to exert its activity.
Although the reactions involved are different, NheI and XhoI, like PARP, require about 10 mM of Mg ²⁺ to exert their activity.
(1) For AQ1, no inhibitory effect was observed at either 3 μg / mL or 15 μg / mL.
(2) On the other hand, AQ2 showed no inhibitory effect at 3 μg / mL, but partially inhibited at 15 μg / mL.
(3) Olaparib was examined at a concentration of 5 μM, but no inhibitory effect was seen (not shown).

Claims (5)

A PARP inhibitor characterized by comprising a leaf extract of peach peach. The PARP inhibitor according to claim 1, wherein the extract has structural units of five gallic acids and a ring-opened hexose. The PARP inhibitor according to claim 1, wherein the extract has C-glycoside type ellagitannin. The PARP inhibitor according to claim 1, wherein the extract comprises one or more of Castalagin and Vescalagin. A therapeutic agent for BRCA1 / 2 gene mutation-positive advanced ovarian cancer comprising the PARP inhibitor according to claim 1 as an active ingredient.