WO2020000704A1 - Utilisation d'un inhibiteur de l'ampk, le composé c, dans un médicament permettant le traitement de tumeurs - Google Patents

Utilisation d'un inhibiteur de l'ampk, le composé c, dans un médicament permettant le traitement de tumeurs Download PDF

Info

Publication number
WO2020000704A1
WO2020000704A1 PCT/CN2018/106620 CN2018106620W WO2020000704A1 WO 2020000704 A1 WO2020000704 A1 WO 2020000704A1 CN 2018106620 W CN2018106620 W CN 2018106620W WO 2020000704 A1 WO2020000704 A1 WO 2020000704A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ampk inhibitor
tumor
ampk
treating tumors
Prior art date
Application number
PCT/CN2018/106620
Other languages
English (en)
Chinese (zh)
Inventor
万晓春
黄诗然
章桂忠
Original Assignee
中国科学院深圳先进技术研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院深圳先进技术研究院 filed Critical 中国科学院深圳先进技术研究院
Publication of WO2020000704A1 publication Critical patent/WO2020000704A1/fr

Links

Images

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to the application of an AMPK inhibitor Compound C in the treatment of tumor drugs.
  • Tumor is a non-hereditary genetic disease. Genes have been changed in normal cells under the action of tumorigenic factors, losing normal regulation of their growth, resulting in abnormal proliferation. Tumor cells have three distinct basic characteristics: immortality, migration, and loss of contact inhibition. The core idea of tumor treatment is to kill and clear tumor cells.
  • one of the mechanisms of tumor treatments commonly used in clinical practice is to induce tumor cells to undergo apoptosis.
  • apoptosis induced by radiotherapy is mainly mediated by Fas, and some cell cycle related proteins and Bcl-2 and Bax also play a key role in this process.
  • Chemotherapy is to induce tumor cells to undergo apoptosis through some chemical drugs to achieve the purpose of suppressing tumor treatment. Drugs such as doxorubicin and 5-fluorouracil can effectively cause cell DNA damage, resulting in cell G1 phase arrest to complete repair or enter apoptosis.
  • Paclitaxel and colchicine which act on microtubules, mediate apoptosis through the Bcl-2 family.
  • chemotherapy is still one of the main strategies for cancer treatment at this stage and in the future.
  • Large toxic side effects and the development of drug resistance are the main obstacles facing tumor chemotherapy.
  • Compound C (Dorsomorphin) is a potent and reversible selective AMPK inhibitor, competing for its ATP binding site. Ki was 109 nM in the cell-free assay. Studies have shown that Compound C selectively inhibits AMPK activity, while other structurally-related kinases include ZAPK, SYK (Spleen Tyrosine Kinase), PKC ⁇ (Protein Kinase, C- ⁇ ), PKA (Protein Kininase A), and JAK3 (Janus and Kinase 3) No significant inhibitory effect. Therefore, at present in the art, Compound C is often used as a specific AMPK inhibitor, and other new uses of Compound C have not been found, such as its use for treating tumors.
  • the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an application method of Compound C, an AMPK inhibitor, to solve the current compound C is only used for specific AMPK inhibitors and the side effects of current methods and drugs for treating cancer Large, prone to technical problems such as drug resistance.
  • Another object of the present invention is to provide a medicament for treating tumors, so as to solve the technical problems of toxic and side effects of existing medicaments for treating tumours, prone to drug resistance, and susceptible to recurrence of tumours.
  • an application method of the AMPK inhibitor Compound C is provided. Specifically, the application of the AMPK inhibitor Compound C in the preparation of a medicine for treating tumors.
  • a medicament for treating tumors in another aspect of the present invention, includes an effective dose of an active ingredient for treating a tumor, and the active ingredient includes an AMPK inhibitor Compound C.
  • the AMPK inhibitor Compound C has a relatively strong effect of inhibiting tumor cell activity and inducing apoptosis of tumor cells, and exerts an anti-hematological tumor effect. Therefore, after preparing the tumor drug by using the AMPK inhibitor Compound C as an active ingredient, the tumor drug can be endowed with a significant effect on inhibiting tumor cell activity and inducing tumor cell apoptosis.
  • the medicine for treating tumors of the present invention uses the AMPK inhibitor Compound C as an active ingredient. Therefore, the medicine for treating tumors can effectively inhibit the activity of tumor cells and induce and promote tumor cell apoptosis to achieve relief and reduction of malignant tumors on the human body. Harm, relieve clinical symptoms, improve quality of life, and prolong life.
  • FIG. 1 is a graph showing the effect of Compound C and Rapamycin reagents of different concentrations on the activity of Jurkat lymphoma cells in Example 11 of the present invention
  • Example 11 of the present invention is a graph showing the effect of Compound C and Rapamycin reagents on K562 lymphoma cell activity in different concentrations in Example 11 of the present invention
  • FIG. 3 is a graph showing the effect of Compound C and control reagent (DMSO) on the apoptosis of Jurkat lymphoma cells in Example 12 of the present invention
  • FIG. 4 is a graph showing the effect of Compound C and control reagent (DMSO) on K562 lymphoma cell apoptosis in Example 12 of the present invention.
  • Tumor refers to a new organism (neogrowth) formed by the body's local tissue proliferation under the action of various tumorigenic factors, because this new organism is mostly a mass-shaped protrusion, also called neoplasm (neoplasm).
  • Compound C (Dorsomorphin): A potent, reversible, and selective AMPK inhibitor with Ki of 109 nM in cell-free assays. Its molecular structure is as follows:
  • AMPK Addenosine Monophosphate-activated Protein Kinase: It is a key sensor of cell energy.
  • the protein kinase can maintain the balance of ATP generation and consumption of eukaryotic cells by sensing the energy state of the cell, that is, energy homeostasis. Its activation helps to correct metabolic disorders and bring the cell metabolism to physiological balance, thus becoming a treatment of metabolic disorders. And possible targets for cancer.
  • Many studies have shown that the activation of AMPK can stimulate the body to produce ATP and provide energy for physiological activities; at the same time, the activation of AMPK can strongly inhibit the synthesis of proteins and fats to reduce the consumption of ATP.
  • the inhibition of AMPK activity by Dorsomorphin almost completely inhibited the proteolytic effect of autophagy in HT-29 cells.
  • the embodiment of the present invention provides an application method of the AMPK inhibitor Compound C.
  • the application of the AMPK inhibitor Compound C in the preparation of a medicine for treating tumors.
  • the AMPK inhibitor Compound C is an active ingredient, which can effectively inhibit tumor cell activity and induce and promote tumor cell apoptosis.
  • the compound AMPK inhibitor Compound C can be used as an effective anti-tumor component to inhibit tumor cell activity and induce and promote tumor cell apoptosis, to alleviate and reduce the harm of malignant tumors to the human body, and to relieve clinical symptoms. , Improve the quality of life and extend the clinical effect of life.
  • the AMPK inhibitor Compound C can inhibit tumor cell activity and promote tumor cell apoptosis.
  • the tumor can be a blood tumor, that is, the AMPK inhibitor Compound C can be used in the preparation of a drug for treating blood tumors.
  • the hematological tumor includes at least one of lymphoma, myeloid leukemia, and myeloma. Wherein, the lymphoma includes T / B lymphoma.
  • AMPK inhibitor Compound C which can inhibit the activity of blood tumor cells and promote the apoptosis of blood tumor cells, it can also be other types of tumors.
  • AMPK inhibitor Compound C when used to prepare a tumor therapy drug, a corresponding dosage form can be prepared according to different modes of administration. Then, the compound AMPK inhibitor Compound C can be compounded with components acceptable to the drug in the corresponding dosage form, such as excipients, etc., and can also be compounded with other anti-tumor active ingredients to form an anti-tumor composite active ingredient.
  • the embodiment of the present invention also provides a medicine for treating tumors.
  • the medicine for treating tumors includes an effective dose of active ingredients for treating tumors, and of course, further pharmaceutically acceptable auxiliary ingredients may be further used.
  • the effective dose refers to an effective amount for treating a tumor, and refers to an amount of a compound of the present invention sufficient to show benefit or clinical significance to an individual.
  • the actual amount or dose administered and the duration of administration will depend on the nature and severity of the disease being prevented or treated, the age and general condition of the subject being prevented or treated, and the Medicine way and so on.
  • the active ingredient includes Compound C, an AMPK inhibitor; of course, as mentioned above, the active ingredient may also include other active ingredients that are effective against tumors.
  • the effect component may be a component that can improve the antitumor effect of the AMPK inhibitor Compound C after being compounded with the AMPK inhibitor Compound C.
  • the content of the AMPK inhibitor Compound C in the medicine for treating tumors is 5-20 ⁇ M.
  • the auxiliary component may be a related auxiliary material of a corresponding dosage form prepared according to the drug administration method of treating a tumor.
  • the excipient is a pharmaceutically acceptable carrier of the AMPK inhibitor Compound C.
  • the carrier includes at least one of an antibody capable of coupling to an AMPK inhibitor Compound C, a targeted recombinant protein, a nanoparticle, and an exosome.
  • the medicine for treating tumors uses the compound AMPK inhibitor Compound C described above as an active ingredient. Therefore, the medicine for treating tumors can effectively inhibit tumor cell activity and induce and promote tumor cell apoptosis to achieve remission and reduction of malignancy.
  • the harm of tumors to the human body alleviates clinical symptoms, improves quality of life, and prolongs life.
  • the medicine for treating tumors can be prepared according to a conventional medicine preparation method.
  • the medicine for treating tumors contains an antibody capable of coupling to an AMPK inhibitor Compound C
  • the antibody can be coupled to AMPK to inhibit the conventional method.
  • Agent Compound C Compound C.
  • Lymphoma cells (Jurkat, K562) were resuspended to 3 ⁇ 10 5 cells / mL and seeded in 12-well plates; 2) Apoptosis was detected after 48 h incubation with Compound C;
  • Annexin V-FITC single positive cells are early apoptotic cells
  • Annexin V-FITC / PI double positive cells are late apoptotic cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la nouvelle utilisation d'un inhibiteur de l'AMPK, le composé C. Spécifiquement, l'invention concerne l'utilisation de l'inhibiteur de composé C dans la préparation d'un médicament pour le traitement de tumeurs. Le composé C peut jouer le rôle de lutte contre les tumeurs hématologiques par le biais de l'inhibition de l'activité des cellules tumorales et de l'induction de l'apoptose chez les cellules tumorales. La nouvelle utilisation de cet inhibiteur de l'AMPK de la présente invention, le composé C, fournit un nouveau médicament pour le traitement de tumeurs hématologiques dans un contexte clinique.
PCT/CN2018/106620 2018-06-29 2018-09-20 Utilisation d'un inhibiteur de l'ampk, le composé c, dans un médicament permettant le traitement de tumeurs WO2020000704A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810695505.2A CN110652515A (zh) 2018-06-29 2018-06-29 AMPK抑制剂Compound C在治疗肿瘤药物中的应用
CN201810695505.2 2018-06-29

Publications (1)

Publication Number Publication Date
WO2020000704A1 true WO2020000704A1 (fr) 2020-01-02

Family

ID=68984663

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/106620 WO2020000704A1 (fr) 2018-06-29 2018-09-20 Utilisation d'un inhibiteur de l'ampk, le composé c, dans un médicament permettant le traitement de tumeurs

Country Status (2)

Country Link
CN (1) CN110652515A (fr)
WO (1) WO2020000704A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115317490A (zh) * 2021-12-24 2022-11-11 南通大学附属医院 化合物bml-275在制备改善鼻咽癌预后的药物中的应用
CN116966307A (zh) * 2022-04-22 2023-10-31 深圳先进技术研究院 Ampk抑制剂联合hdac抑制剂在制备肿瘤治疗的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117153A1 (fr) * 2008-03-20 2009-09-24 George Mason Intellectual Properties, Inc. Voie ampk servant de marqueur théranostique pour la leucémie à lignée mixte (mll)
CN103655573A (zh) * 2013-10-11 2014-03-26 泸州医学院 吡唑并嘧啶类化合物在制备转录抑制剂药物中的用途
CN104800847A (zh) * 2014-01-29 2015-07-29 中国科学院上海巴斯德研究所 Bmp通路抑制剂在制备卡波氏肉瘤病毒感染疾病治疗药物中的用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2270229A1 (fr) * 2006-09-12 2011-01-05 The General Hospital Corporation Inhibiteurs de signalisation du bone morphognétic protéine (bmp) pour utilisation thérapeutique
US8642334B2 (en) * 2009-02-17 2014-02-04 Memorial Sloan Kettering Cancer Center Methods of neural conversion of human embryonic stem cells
EP2733205B1 (fr) * 2012-11-20 2018-01-10 Centro De Investigacíon Biomédica En Red De Enfermedades Neurodegenerativas Ciberned Neurones moteurs supérieurs cortico-spinaux, procédés et compositions permettant de différencier des cellules souches neurales par modulation de la signalisation des récepteurs cannabinoïdes CB1 et leurs utilisations
US10786536B2 (en) * 2013-10-29 2020-09-29 Vestion, Inc. Cardiac neural crest cells and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117153A1 (fr) * 2008-03-20 2009-09-24 George Mason Intellectual Properties, Inc. Voie ampk servant de marqueur théranostique pour la leucémie à lignée mixte (mll)
CN103655573A (zh) * 2013-10-11 2014-03-26 泸州医学院 吡唑并嘧啶类化合物在制备转录抑制剂药物中的用途
CN104800847A (zh) * 2014-01-29 2015-07-29 中国科学院上海巴斯德研究所 Bmp通路抑制剂在制备卡波氏肉瘤病毒感染疾病治疗药物中的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HE, MEILIAN ET AL.: "SIRT1 and AMPK Pathways Are Essential for the Proliferation and Survival of Primary Effusion Lymphoma Cells", THE JOURNAL OF PATHOLOGY, vol. 242, no. 3, 1 July 2017 (2017-07-01), pages 309 - 321, XP055669906, ISSN: 0022-3417, DOI: 10.1002/path.4905 *
JANG, J.E. ET AL.: "AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells", CLINICAL CANCER RESEARCH, vol. 23, no. 11, 1 June 2017 (2017-06-01), pages 2781 - 2794, XP055669916, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-16-1903 *

Also Published As

Publication number Publication date
CN110652515A (zh) 2020-01-07

Similar Documents

Publication Publication Date Title
Dziegielewska et al. T-type calcium channels blockers as new tools in cancer therapies
Liu et al. Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells
US8993587B2 (en) Combination of syrosingopine and mitochondrial inhibitors for the treatment of cancer and immunosuppression
WO2022228323A1 (fr) Application de ly3009120 dans la préparation de médicaments pour le traitement de néoplasmes myéloprolifératifs
US10980768B2 (en) Composition containing carboplatin and use
Lin et al. Emodin inhibits migration and invasion of MHCC‑97H human hepatocellular carcinoma cells
Jackson et al. Pharmacological inhibition of pleckstrin homology domain leucine-rich repeat protein phosphatase is neuroprotective: differential effects on astrocytes
Liu et al. Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy
CN117298104B (zh) Elovl6-in-2在制备mycn扩增型神经母细胞瘤药物中的应用
WO2020000704A1 (fr) Utilisation d'un inhibiteur de l'ampk, le composé c, dans un médicament permettant le traitement de tumeurs
EP3412287A1 (fr) Application de zl-n-91, inhibiteur de phosphodiestérase 4, dans la préparation de médicaments pour la prolifération et les métastases des cellules cancéreuses du poumon
WO2018064851A1 (fr) Utilisation de sildénafil à faible dose comme médicament antitumoral
Tan et al. Erchen Plus Huiyanzhuyu Decoction Inhibits the Growth of Laryngeal Carcinoma in a Mouse Model of Phlegm‐Coagulation‐Blood‐Stasis Syndrome via the STAT3/Cyclin D1 Pathway
CN110151775B (zh) 17-dmag在制备抑制儿童急性淋巴细胞白血病药物中的应用
TW202034919A (zh) 西奧羅尼用於小細胞肺癌的治療
CN112263578B (zh) Tipranavir在制备杀伤肿瘤干细胞和肿瘤细胞的癌症治疗药物中的用途
TW201206457A (en) Reishi polysaccharide-based compositions and methods for treatment of cancer
CN109106715B (zh) 8-羟基喹啉类药物或其盐在制备用于治疗与brd4相关的疾病的药物中的应用
Ota et al. Therapeutic strategies for head and neck cancer based on p53 status
CN108619488B (zh) 一种治疗肿瘤的联合用药方法
CN110840877A (zh) 右旋地衣酸单独或联合紫杉醇在制备治疗和抗肺鳞癌药物上的应用
CN110585207A (zh) 莲心碱在制备防治脑胶质瘤药物中的应用
Zhang et al. Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis
WO2013169390A1 (fr) Zéaxanthine utilisée pour le traitement des tumeurs
WO2015188738A1 (fr) Nouvelle utilisation de l'ibrutinib

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18924941

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 17.05.2021)

122 Ep: pct application non-entry in european phase

Ref document number: 18924941

Country of ref document: EP

Kind code of ref document: A1