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WO2018199727A1 - Composition pharmaceutique contenant un activateur de nm23, destinée à l'inhibition de métastases cancéreuses - Google Patents

Composition pharmaceutique contenant un activateur de nm23, destinée à l'inhibition de métastases cancéreuses Download PDF

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Publication number
WO2018199727A1
WO2018199727A1 PCT/KR2018/005036 KR2018005036W WO2018199727A1 WO 2018199727 A1 WO2018199727 A1 WO 2018199727A1 KR 2018005036 W KR2018005036 W KR 2018005036W WO 2018199727 A1 WO2018199727 A1 WO 2018199727A1
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Prior art keywords
cancer
formula
pharmaceutical composition
metastasis
compound
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PCT/KR2018/005036
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English (en)
Korean (ko)
Inventor
이공주
이희윤
이제진
서은경
이은선
김황석
이홍수
Original Assignee
이화여자대학교 산학협력단
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Priority claimed from KR1020180049329A external-priority patent/KR102034958B1/ko
Application filed by 이화여자대학교 산학협력단 filed Critical 이화여자대학교 산학협력단
Priority to CN201880028168.XA priority Critical patent/CN110573147B/zh
Priority to EP18789847.3A priority patent/EP3616692A4/fr
Priority to US16/609,094 priority patent/US11389411B2/en
Priority to JP2019558495A priority patent/JP2020517710A/ja
Publication of WO2018199727A1 publication Critical patent/WO2018199727A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon

Definitions

  • the present invention relates to a pharmaceutical composition for inhibiting cancer metastasis comprising the novel Nm23 activator.
  • Cancer metastasis is one of the most important factors in determining the prognosis of cancer patients and is the main process of determining death from cancer. In the treatment of cancer, a lot of efforts have been made for the survival of patients such as surgery, radiation therapy, and chemotherapy, but efforts to improve the survival of cancer patients continue.
  • the field of studying cancer metastasis is one of the last strategies to overcome cancer, and the study of cancer metastasis suppressors is essential for developing metastasis suppressing drugs.
  • Nm23 is a gene encoding a protein involved in the development and differentiation of normal tissues, and a decrease in the expression of Nm23 has been reported in various metastatic cell lines.
  • the Nm23 protein which generally consists of 150 to 180 amino acids, comprises a leucine zipper motif and has a dinucleotide phosphate kinase (NDPK) activity.
  • NDPK dinucleotide phosphate kinase
  • Nm23-H1 has been found to play an important role in cancer metastasis and various other cellular mechanisms such as cell proliferation, embryonic development, differentiation, tumor formation, and the like.
  • 1 is a diagram showing the stages of cancer metastasis.
  • the metastasis of cancer begins at various stages, where cancer cells begin to infiltrate blood vessels in the primary tumor tissue, moving through the vessels and surviving to form new colonies at the secondary site. It happens through the process.
  • Nm23-H1 is involved in cancer metastasis inhibitory activity at various stages such as invasion / intravasation, extravasation, metastatic colonization, etc. in the process of cancer metastasis.
  • Horak CE et al., The role of metastasis suppressor genes in metastatic dormancy., APMIS. (2008) Jul-Aug; 116 (7-8): 586-601).
  • Nm23 affects cancer metastasis and development
  • NDPK Nucleotide diphosphate kinase
  • ATP is used to convert NDP (UDP, GDP, CDP) into NTP (UTP, GTP, CTP).
  • the protein that converts was found to be an enzyme that regulates the amount of NTP in the cell.
  • 2 is a schematic diagram showing NDPK activity of Nm23.
  • overexpression of Nm23-H1 has been shown to be closely associated with decreased cancer cell invasion (Lee E, et al., Multiple functions of Nm23-H1 are regulated by oxido-reduction system., PLoS One. (2009) ) Nov 23; 4 (11): e7949).
  • the present inventors completed the present invention by carrying out research and development on a small molecule substance that modulates the activity of Nm23 involved in the cancer metastasis process.
  • One object of the present invention to provide a pharmaceutical composition for inhibiting cancer metastasis comprising a novel activator of Nm23.
  • a pharmaceutical composition comprising a compound represented by Formula 1 of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may act as an activator of Nm23-H1 and / or Nm23-H2 to metastasize cancer cells and Inhibits infiltration; Therefore, Nm23 activator according to the present invention can be very useful as a pharmaceutical composition for inhibiting metastasis of cancer.
  • 1 is a schematic diagram showing the stage of metastasis of cancer.
  • FIG. 2 is a schematic diagram showing NDPK activity of Nm23.
  • Figure 3 is a diagram confirming the NDPK activity for the compound of formula 2-1.
  • 5 is a diagram showing the results of plasma resonance analysis.
  • FIG. 6 is a diagram illustrating the change in cell morphology and treatment of Rac1 activity in each cell line by treating the compound of formula 2-1 to two breast cancer cell lines.
  • FIG. 7 is a diagram verifying the inhibition of invasion and migration of the compound of formula 2-1 on MDA-MB-231 cells.
  • FIG. 8 is a diagram showing the metastasis inhibitory activity of the compound of formula 2-1 in a breast cancer metastasis model.
  • FIG. 9 is a diagram showing the volume of cancer, and mouse weight change according to the treatment of the compound of formula 2-1.
  • FIG. 10 is a diagram showing metastasis inhibitory activity of the compound of formula 2-1 in a breast cancer metastasis model.
  • the present inventors completed the present invention by uncovering compounds that enhance the NDPK activity of Nm23.
  • One embodiment of the present invention is a pharmaceutical composition for inhibiting cancer metastasis comprising a compound represented by the following formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Ring A is cyclohexene, cyclohexane or benzene.
  • the compound represented by Chemical Formula 1 is a compound represented by any one of the following Chemical Formulas 2 to 4.
  • Stereoisomers in the present invention may exist as optical isomers, racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. Such isomers can be separated by conventional techniques such as column chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds represented by Formula 1 can be stereospecifically synthesized using optically pure starting materials and / or reagents in known arrangements.
  • the stereoisomer of the compound represented by Formula 1 is E form.
  • the compound represented by Chemical Formula 1 may be represented by any one of the following Chemical Formulas 2-1 to 4-1.
  • the compounds of Formulas 2-1 to 4-1 may be prepared by, for example, the process shown in Preparation Examples 1 to 3 of the present invention, but is not limited thereto.
  • pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ions, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, prepared with calcium, potassium, sodium and magnesium, Inorganic acid salts prepared with iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid Organic acid salts prepared with acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like; Sulfonic acid salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-tolu
  • the pharmaceutical composition of the present invention may act as an activator of Nm23-H1, Nm23-H2 or Nm23-H1 and Nm23-H2.
  • the compound of formula 1 of the present invention interacts with Nm23-H1 to form a hydrophobic pocket to expose the active site of Nm23-H1 and kpn-loop, which is known to be most important for regulating NDPK activity. And allostericly increase NDPK activity.
  • the compound of formula 1 of the present invention may exhibit the same activity for Nm23-H2, which is another subtype of Nm23 (FIG. 3 and Table 2).
  • the compound represented by Formula 1 of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof may further promote the activity of Nm23 in the presence of ATP (FIG. 4).
  • the cancer is breast cancer, lung cancer, melanoma, prostate cancer, colon cancer, bladder cancer, bone cancer, blood cancer, thyroid cancer, parathyroid cancer, bone marrow cancer, rectal cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, stomach cancer, It may be any one selected from the group consisting of tongue cancer, skin cancer, brain tumor, uterine cancer, head or neck cancer, gallbladder cancer, oral cancer, colon cancer, anal muscle cancer, central nervous system tumor, liver cancer and colon cancer.
  • the pharmaceutical composition of the present invention does not increase the efficacy, but may further include ingredients that are commonly used in the pharmaceutical composition to improve the smell, taste, time and the like.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive.
  • Pharmaceutically acceptable additives include, for example, starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, malt, gum arabic, pregelatinized starch, corn starch, powdered cellulose, Hydroxypropyl cellulose, opiodry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, white sugar, dextrose, sorbitol and talc, but are not limited thereto.
  • the pharmaceutical composition may further include one or more active ingredients exhibiting the same or similar medicaments in addition to the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and can be formulated for human or veterinary use for oral or parenteral use.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants can be used.
  • Solid form preparations for oral administration include tablets, pills, powders, granules and capsules and the like, and such solid form preparations may be used in pharmaceutical compositions comprising the compounds of the present invention at least one excipient such as starch, calcium carbonate. , Can be mixed with sucrose, lactose or gelatin.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
  • injectable esters such as ethyl oleate
  • suppositories witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally according to a desired method, and may be external or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection during parenteral administration. Injection may be selected, but is not limited thereto.
  • composition of the present invention may be used alone, but may be used in combination with various cancer treatment methods, such as radiation therapy and chemotherapy, in order to increase the treatment efficiency.
  • Another embodiment of the present invention is a method for inhibiting cancer metastasis comprising administering a therapeutically effective amount of a composition comprising a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the present invention is a use for the manufacture of a drug for inhibiting cancer metastasis of the compound represented by the formula (1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention can be administered to a subject to inhibit cancer metastasis.
  • the term "individual” has a disease caused by cancer or a direct or indirect cause thereof, and includes a human including a disease whose symptoms may be improved by administering the pharmaceutical composition of the present invention. , But not limited to mammals such as sheep, pigs, goats, and dogs.
  • the term "administration" means introducing a pharmaceutical composition of the present invention to a subject in any suitable manner.
  • the route of administration can be administered orally or parenterally via any route as long as it can reach the desired tissue.
  • the pharmaceutical composition of the present invention may be administered by any device that allows migration to target cells.
  • the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is weight, sex, age, health condition, severity of the patient. , The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently, and other factors well known in the medical arts.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with the conventional therapeutic agent in combination administration. It may be single or multiple doses.
  • NBuLi (2.48 M in Hx) (1.95 equiv) was added to tetrahydrofuran in which diethyl 3,4-dimethoxybenzylphosphonate (2.0 equiv) was dissolved at 0 ° C.
  • the mixture was mixed at room temperature for 30 minutes and then lowered to 0 ° C. to (1 S , 2 S ) -2- (3,4-dimethoxyphenyl) cyclohex-3-enecarbaldehyde (1.0 equiv) DMPU (5.0 equiv) was dissolved in THF and added using cannula.
  • the mixture was mixed overnight at room temperature and then the reaction was terminated with ammonium chloride and water.
  • the mixture was extracted with ethyl acetate, dried over MgSO 4 , concentrated and separated on silica gel using cylindrical chromatography.
  • Formula 2-1 may also be prepared by the following Scheme 5.
  • o-bromobenzaldehyde (1.0 equiv) was dissolved in DMF, followed by 3,4-dimethoxyphenylboronic acid (1.0 equiv), 2 M Na 2 CO 3 (3.0 equiv) and Pd (PPh 3 ) 4 (0.01 equiv) ) was added at room temperature.
  • the mixture was mixed overnight at 80 ° C. and diluted with ethyl acetate. Then, the reaction was terminated by adding ammonium chloride and water. Then, the mixture was extracted with ethyl acetate and the organic layer was dried over MgSO 4 . The mixture was filtered to concentrate the combined organic layers, and then separated on silica gel using cylindrical chromatography.
  • NDPK assay buffer 20 mM HEPES, 3 mM MgCl 2
  • test substance compound 2-1, 3-1 or 4-1 compound
  • Cultured and cell based NDPK analysis was performed.
  • Cell lysates obtained from 5,000 K MDA-MB-231 cells lysed with protease inhibitor cocktail and NDPK assay buffer were centrifuged at 8,000 rpm for 10 minutes at 4 ° C. 40 ⁇ L of the lysate was incubated with the test material for 5 minutes and then reacted with NDPK by adding 50 ⁇ M UDP.
  • ATP consumption was assessed by the ATP Decision Kit (Molecular probe, USA).
  • ITC experiments were performed using the ITC200 instrument (Malvern Inc.) and data were analyzed using the ORIGIN 7.0 program.
  • the concentration of Nm23-H1 protein in the cells was 30 ⁇ M and the syringe contained 300 ⁇ M of activator or 1 mM ATP.
  • the active agent was prepared in DMSO (Dimethyl sulfoxide) at a concentration of 50 mM and stored at -20 ° C.
  • ITC buffer contained 20 mM HEPES at pH 7.5, 150 mM NaCl, 3 mM MgCl 2 and up to 2% DMSO. Titration was injected 20 times, 2 ⁇ L each at 25 ° C., and 150 sec intervals.
  • the titration data is a nonlinear least-squares-fitting algorithm with three floating variables: stoichiometry (N), dissociation constant (KD), and change of enthalpy of interaction. curve-fitting algorithm).
  • Nm23-H1 (1 mg / mL) in 10 mM SA buffer at pH 4.5 was quenched at 20 ⁇ L / min on a carboxymethyl dextran hydrogel (CMDH) surface sensor chip (Reichert Technologies, Depew, NY). While standard amino coupling was used until saturation was achieved.
  • CMDH carboxymethyl dextran hydrogel
  • K D is a value obtained by calculating K d / K a .
  • NMac1 is a diagram confirming the activity of NDPK to the compound of formula 2-1.
  • the compound of formula 2-1 in each figure is represented by NMac1.
  • NDPK activity of Nm23-H1 is increased according to the concentration of the compound of Chemical Formula 2-1.
  • Km-type activity exhibited the same tendency as the existing enzyme activator.
  • the NDPK activator increases the activity of NDPK by increasing the affinity for the substrate NTP.
  • the cell-based NDPK activity is increased with the concentration of the compound of formula 2-1.
  • FIG. 4 is a diagram showing the results of performing isothermal titration calorimetry (isothermal calorimetry) on the compound of formula 2-1.
  • isothermal calorimetry isothermal calorimetry
  • FIG. 5 is a diagram showing the results of plasma resonance analysis. As a result of Figure 5, it was confirmed that Nm23-H1 and the compound of the present invention is directly bonded.
  • MDA-MB-231 cells were cultured in 100 mm dishes and treated with the indicated concentrations of Formula 2-1 compound or 0.05% DMSO for 16 hours.
  • the active Rac1 pulldown assay was performed according to the manufacturer's instructions (Thermo Fisher Scientific).
  • MDA-MB-231 cells were cultured to 50-70% levels on Secureslip TM (Sigma) cell culture glass cover slips and then treated for various hours in the presence or absence of the compound of Formula 2-1.
  • the cells were gently washed with cold HBSS and then fixed in RBS with HBSS containing 4% paraformaldehyde at room temperature for 10 minutes. After washing with HBSS, infiltration with 0.1% Triton X-100 was performed at room temperature for 10 minutes, and after washing twice with HBSS, HBSS containing 3% BSA, 0.2% Tween 20 and 0.2% gelatin for 1 hour at room temperature. Blocking was performed, and the primary antibody was incubated at 37 ° C. for 2 hours, followed by 1 hour of incubation with a fluorochrome-conjugated species-specific secondary antibody.
  • the cells were treated with the compound of formula 2-1 for 16 hours when the cells were 70% filled. 1 x 10 5 cells were suspended in media without FBS and added over a Boyden chamber membrane. Culture medium containing 10% FBS was added to the membrane bottom. The chamber was incubated at 37 ° C., 5% CO 2 for 4 hours. The migrated cells were fixed and stained with crystal violet / methanol. Photos were taken and the migrated cells were counted and normalized to control cells.
  • FIG. 6 is a diagram illustrating the change in cell morphology and treatment of Rac1 activity in each cell line by treating the compound of formula 2-1 to two breast cancer cell lines.
  • FIG. 6A illustrates a case where the compound of Formula 2-1 was treated using confocal microscopy, and when the F-actin change of MDA-MB-231 cells was observed, the ruffle was reduced. Increasing contact between cells can be seen. This means inhibiting the activity of Rac1 involved in cell migration of Nm23-H1 and reducing cell mobility.
  • Figure 6B is a diagram measuring the change in shape and the activity of Rac1 according to the compound of formula 2-1 in MDA-MB-231 cells, a triple negative breast cancer cell line.
  • the pull-down assay of the activated Rac1 it can be seen that the compound of formula 2-1 of the present invention lowers the activity of Rac1 in a concentration-dependent manner.
  • FIG. 6C and FIG. 6D it can be seen that disappearing by knockdown of Nm23-H1 inhibits Rac1 activity through Nm23-H1.
  • Figure 7 is a diagram verifying the inhibition of infiltration and migration of the compound of formula 2-1 to MDA-MB-231 cells.
  • Figure 7A is a diagram showing the results of infiltration analysis, transwell migration analysis in MDA-MB-231 cells, a triple negative breast cancer cell line.
  • FIG. 7B is a diagram showing Nm23-H1 activity of the compound of formula 2-1 in A549 cells, a lung cancer cell line. Referring to the results of FIG. 7B, it can be seen that the compound of Formula 2-1 of the present invention reduces the wound healing and Matrigel infiltration by concentration in A549 cells.
  • FIG. 7C is a diagram showing Nm23-H1 and Nm23-H2 activities of the compound of formula 2-1.
  • FIG. 7C when the effects of the compounds of Formula 2-1 are all reduced by knockdown of Nm23-H1 and Nm23-H2, the in vitro metastasis inhibitory activity of Formula 2-1 is determined via Nm23-H1 and Nm23-H2. You can see what happens.
  • the metastasis inhibitory activity of the compound of formula 2-1 of the present invention was applied to a breast cancer metastasis model using MDA-MB-231 luc cells in order to confirm in a real animal model. After injection of MDA-MB-231 cells into the mammary fat pad of nude mice, when the tumor size reached 100 mm, the compound of formula 2-1 was injected daily at 10 mg / kg. The metastasis to the lung was observed during the week.
  • FIG. 8 is a diagram showing metastasis inhibitory activity of the compound of formula 2-1 in a breast cancer metastasis model. As a result of Figure 8 it can be seen that the metastasis to the lung in the group treated with the compound of formula 2-1 of the present invention.
  • FIG. 9 is a view showing the changes in the volume and weight of cancer according to the treatment of the compound of formula 2-1. As a result of FIG. 9, it was confirmed that the volume of the cancer was reduced in the group treated with the compound of formula 2-1 of the present invention.
  • FIG. 10 is a diagram showing metastasis inhibitory activity of the compound of formula 2-1 in a breast cancer metastasis model. As a result of Figure 10, it was confirmed that the cells metastasized to the lung significantly reduced.
  • the compound represented by the formula (1) according to the present invention can be used as a pharmaceutical composition effective in inhibiting metastasis of cancer by increasing NDPK activity of Nm23.

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Abstract

La présente invention concerne une composition pharmaceutique permettant d'inhiber la métastase cancéreuse, la composition pharmaceutique contenant en tant que principe actif un composé activateur de l'inhibiteur de la métastase cancéreuse Nm23, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Le composé selon la présente invention inhibe la métastase de cellules cancéreuses par stimulation de l'activité de Nm23, qui est associée à la métastase cancéreuse, et peut donc être avantageusement utilisé en tant que composition pharmaceutique visant à inhiber la métastase cancéreuse.
PCT/KR2018/005036 2017-04-28 2018-04-30 Composition pharmaceutique contenant un activateur de nm23, destinée à l'inhibition de métastases cancéreuses WO2018199727A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201880028168.XA CN110573147B (zh) 2017-04-28 2018-04-30 用于抑制癌症转移的包含nm23活化剂的药物组合物
EP18789847.3A EP3616692A4 (fr) 2017-04-28 2018-04-30 Composition pharmaceutique contenant un activateur de nm23, destinée à l'inhibition de métastases cancéreuses
US16/609,094 US11389411B2 (en) 2017-04-28 2018-04-30 Pharmaceutical composition, containing NM23 activator, for inhibiting cancer metastasis
JP2019558495A JP2020517710A (ja) 2017-04-28 2018-04-30 Ｎｍ２３活性剤を含む癌転移抑制用医薬組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0055151 2017-04-28
KR20170055151 2017-04-28
KR1020180049329A KR102034958B1 (ko) 2017-04-28 2018-04-27 Nm23 활성제를 포함하는 암 전이 억제용 약학적 조성물
KR10-2018-0049329 2018-04-27

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Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
C HU ET AL., J . NAT PROD., vol. 74, 2011, pages 1817
CHAE, S. W. %: "In vitro and in vivo evaluation of phenylbutenoid dimers as inhibitors of P-glycoprotein", JOURNAL OF NATURAL PRODUCTS, vol. 76, no. 12, 2013, pages 2277 - 2281, XP055531659 *
CHUNG, S. Y.: "Potent modulation of P-glycoprotein activity by naturally occurring phenylbutenoids from Zingiber cassumunar", PHYTOTHERAPY RESEARCH, vol. 23, no. 4, 2009, pages 472 - 476, XP055531666 *
HORAK CE ET AL.: "The role of metastasis suppressor genes in metastatic dormancy", A PMIS, vol. 116, no. 7-8, July 2008 (2008-07-01), pages 586 - 601
KUROYANAGI, M.: "Further characterization of the constituents of a thai medicinal plant, Zingiber cassumunar Roxb", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 28, 1980, pages 2948 - 2959, XP055531671 *
LEE E ET AL.: "Multiple functions of Nm23-H1 are regulated by oxido reduction system", PLOS ONE, vol. 4, no. 11, 23 November 2009 (2009-11-23), pages e7949, XP055154142, DOI: 10.1371/journal.pone.0007949
LIMJ ET AL.: "Cell-permeable NM23 blocks the maintenance and progression of established pulmonary metastasis", CANCER RES., vol. 71, no. 23, 1 December 2011 (2011-12-01), pages 7216 - 25
MATSUDA, H. %: "Invasion inhibitors of human fibrosarcoma HT 1080 cells from the rhizomes of Zingiber cassumunar: structures of phenylbutanoids, cassumunols", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 59, no. 3, 2011, pages 365 - 370, XP009193792 *
PALMIERI D ET AL.: "Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer", J NATL CANCER INSL, vol. 97, no. 9, 4 May 2005 (2005-05-04), pages 632 - 42
See also references of EP3616692A4 *
ZHAO, D. -D. %: "Compounds from Dryopteris fragrans (L.) Schott with cytotoxic activity", MOLECULES, vol. 19, no. 3, 2014, pages 3345 - 3355, XP055531656 *

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