WO2020125551A1 - Application de thioguanine dans la préparation de médicaments pour le traitement, l'amélioration ou la prévention de tumeurs - Google Patents

Application de thioguanine dans la préparation de médicaments pour le traitement, l'amélioration ou la prévention de tumeurs Download PDF

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WO2020125551A1
WO2020125551A1 PCT/CN2019/125154 CN2019125154W WO2020125551A1 WO 2020125551 A1 WO2020125551 A1 WO 2020125551A1 CN 2019125154 W CN2019125154 W CN 2019125154W WO 2020125551 A1 WO2020125551 A1 WO 2020125551A1
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cancer
saicar
tumor
high expression
paics
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PCT/CN2019/125154
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English (en)
Chinese (zh)
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朱威
潘武广
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广州君赫生物科技有限公司
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Publication of WO2020125551A1 publication Critical patent/WO2020125551A1/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
    • A61K31/33—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
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the new application of thioguanine, in particular to the application of thioguanine in the preparation of medicines for treatment, improvement or prevention of tumors.
  • Tumors especially malignant tumors, seriously threaten people's health.
  • the pathogenesis of tumors is diverse, because different tumors have different mechanisms, resulting in different responses to different compounds.
  • Chemotherapy drugs have a certain therapeutic effect on most tumors, mainly because they have a broad-spectrum lethal effect on cells.
  • Compounds that do not have a general lethal effect on cells are often only effective for specific tumors, but not for other tumors, and even have the risk of promoting tumor progression. Therefore, its use is severely restricted.
  • Pyruvate kinase isoenzyme 2 (Pyruvate kinase isoform M2, PKM2), as an important enzyme in the metabolic process, is highly expressed in rapid proliferation and most tumor cells, and has a huge impact on tumor cell metabolism and growth [3, 4].
  • various pharmacological agents targeting PKM2 enzyme activity affect cell growth and proliferation [5, 6], which also suggests that by targeting PKM2 enzyme activity as a representative, further changes in the way of tumor metabolism have become a new approach to cancer treatment [ 7].
  • Purine anabolic metabolism is a ubiquitous and very important biological metabolism of organisms. Its products AMP and GMP not only provide raw materials for the biosynthesis of DNA and RNA in the organism, but also provide many key coenzymes (NAD, NADP, FAD and CoA) in the body. ), signaling molecules (such as cAMP) and important energy molecules ATP provide the necessary purine bases for their synthesis. It can be seen that purine anabolism is at the core of the entire metabolic network. Purine synthesis includes de novo purification (synthesis) and salvage pathway (salvage pathway).
  • ADSL enzyme adenyl succinate lyase
  • SAICAR ribose-50-phosphate
  • PAICS is highly expressed in acute lymphocytic leukemia, lung cancer, glioma, prostate cancer, and rectal cancer, and can be used as a prognostic marker for stage III colorectal cancer [11-13].
  • SAICAR is highly accumulated under glucose-limited conditions, which changes the energy levels, sugar uptake and lactic acid production in tumor cells, and these phenomena have not occurred in adult epidermal cells and lung fibroblasts [14, 15].
  • SAICAR can induce the enzymatic activity of PKM2 and promote the survival of tumor cells [14], and the combination of SAICAR-PKM2 can induce the phosphorylation of Erk1/2, high concentration of SAICAR can also induce the up-regulated expression of oncogene myc [15], these SAICAR, which accumulates abnormally in the de novo anabolic pathway of adenine, promotes the proliferation and survival of tumor cells.
  • Aminoimidazole succinylcarbamoyl nucleotide synthetase/aminoimidazole nucleotide carboxylase namely PAICS (phosphoribosylaminoimidazole succinocarboxamide/synthetase/phosphoribosylaminoimidazole carboxylase) is an important bifunctional enzyme in the de novo synthesis of purine, which has SAICAR synthesis Enzymes (4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase, SAICARs) and AIR carboxylase (5-aminoimidazole ribonucleotide carboxylase, AIRc) function, catalyze the de novo synthesis of purines in the sixth and seventh reactions, in which A key reaction process of
  • DB00352 https://www.drugbank.ca/drugs/DB00352
  • Tioguanine structural formula: Chinese name: thioguanine.
  • the main uses of thioguanine are as follows:
  • Antitumor drugs It can relieve acute leukemia and chronic myeloid leukemia. Large doses have a good effect on choriocarcinoma.
  • Protein kinase activator It is a derivative of adenosine cyclophosphate, its function and use are the same. It can also be used for myocarditis, cardiogenic shock, and submental hemorrhage after surgery. When the dosage is large, there may be drowsiness, dizziness, vertigo, fatigue, loss of appetite, nausea, vomiting, etc.
  • Antitumor drugs It is a kind of purine antimetabolite. It is a homologue of DNA bases and can be incorporated into DNA molecules as a wrong base, thereby affecting the synthesis and function of DNA. It mainly acts on S phase and is a cell cycle specific drug. For the treatment of various types of leukemia, acute leukemia is more commonly used.
  • 6-TG ribonucleotide In the human body to be active.
  • the action of this product is similar to that of mercaptopurine.
  • 6-TG ribonucleotide Through the inhibition of guanylate kinase, the phosphorylation of guanosine monophosphate (GMP) to guanosine diphosphate (GDP) can be prevented. After being metabolized to deoxyribose triphosphate, this product can be incorporated into DNA, thus further inhibiting the biosynthesis of nucleic acids, mercaptopurine has no such effect.
  • This product is effectively cross-resistant to mercaptopurine, and combined with cytarabine and other drugs can improve the efficacy.
  • Hexokinase 2 isis a key, mediator of aerobic glycolysis, tumors, tumor, growth, human glioblastoma, multiforme. J Exp, Med, 2011.208(2): p.313-26.
  • the purpose of the present invention is to provide the application of thioguanine in the preparation of drugs for treating, improving or preventing tumors.
  • the first aspect of the present invention provides:
  • Thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites are used in the preparation of drugs for treatment, improvement or prevention of tumors,
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
  • the tumor is selected from the group consisting of lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cells Cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
  • the tumor has any of the following characteristics:
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • the drug also includes at least one compound and/or agent that has a therapeutic effect on the tumor.
  • the second aspect of the present invention provides:
  • the compound is thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites;
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
  • the tumor is selected from the group consisting of lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cells Cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
  • the tumor has any of the following characteristics:
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • the third aspect of the present invention provides:
  • a composition for treating, improving or preventing tumors is provided.
  • the active ingredients of the composition include: thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites;
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
  • the tumor is selected from the group consisting of lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cells Cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
  • the tumor has any of the following characteristics:
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • the composition also includes at least one compound and/or agent that has a therapeutic effect on the tumor.
  • the fourth aspect of the present invention provides:
  • a method for treating, ameliorating or preventing tumors which includes administering to a patient a therapeutic amount, an improved amount or a preventive amount of thioguanine and its pharmaceutically acceptable derivatives, prodrugs, and active metabolites,
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
  • the tumor is selected from the group consisting of lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cells Cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
  • the tumor has any of the following characteristics:
  • the amount of SAICAR is higher than normal, there is excessive accumulation of SAICAR, SAICAr or S-Ado;
  • it also includes administering at least one compound and/or agent that has a therapeutic effect on the tumor.
  • thioguanine has a good inhibitory effect on some tumor cells, while the inhibitory effect on some tumor cells is significantly weakened. This characteristic of thioguanine is different from most chemotherapy drugs and has its unique and unknown pattern.
  • the inventors based on the TCGA database (The Cancer Genome Atlas) about 10,000 samples of gene expression bioinformatics analysis, combined with further cell biology experiments, found and confirmed that thioguanine on PAICS gene abnormalities Highly expressed cancer has a significant inhibitory effect (as shown in Figure 1, Table 1, Table 2), can treat lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, bile duct cancer, Cancers with abnormally high expression of PAICS genes, such as esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
  • TCGA database The Cancer Genome Atlas
  • Cancers such as paraganglioma and non-abnormally high expression of PAICS genes have no significant therapeutic effect, proving that thioguanine can be developed as a new targeted anticancer drug for cancers with abnormally high expression of oncogene PAICS.
  • Figure 1 shows the PAICS gene expression of different tumors.
  • thioguanine has a significant inhibitory effect on cancers with abnormally high expression of PAICS gene ( Figure 1 , Table 1, Table 2), can treat lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioblastoma, head and neck scales Cancers with abnormally high expression of PAICS genes such as squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia, and those with abnormally high expression of PAICS genes such as renal cancer, cutaneous melanoma, pheochromocytoma, and paraganglioma Cancer has no significant therapeutic effect, proving that thioguanine can be developed as a new targeted anti-cancer drug for cancers with abnormally high expression of oncogene PAICS.
  • ADSL gene-deficient nematodes and ADSL-deficient transgenic mice have excessive accumulation of SAICAR, and their phenotype is similar to the high expression of PAICS gene.
  • the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.
  • thioguanine pharmaceutically acceptable derivatives, prodrugs and active metabolites have significant effects on tumors with high expression of PAICS genes caused or promoted by the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. Therapeutic effect.

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

Abstract

La présente invention concerne une application de thioguanine dans la préparation de médicaments pour le traitement, l'amélioration ou la prévention de tumeurs; la thioguanine a un effet inhibiteur significatif sur le cancer caractérisé par une expression anormalement Élevée du gène PAICS.
PCT/CN2019/125154 2018-12-19 2019-12-13 Application de thioguanine dans la préparation de médicaments pour le traitement, l'amélioration ou la prévention de tumeurs WO2020125551A1 (fr)

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CN201811557839.X 2018-12-19
CN201811557839 2018-12-19

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105056238A (zh) * 2015-09-22 2015-11-18 郑嘉雯 一种具有抗肿瘤活性的药物组合物及其制备方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105056238A (zh) * 2015-09-22 2015-11-18 郑嘉雯 一种具有抗肿瘤活性的药物组合物及其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"6-硫鸟嘌呤老药新用 (Non-official translation: 6-Thioguanine, a Conventional Drug in New Use)", 中国处方药 (JOURNAL OF CHINA PRESCRIPTION DRUG), vol. 13, no. 4, 15 April 2015 (2015-04-15), DOI: 20200304154840X *
"硫鸟嘌呤6-Thioguanine (6-Thioguanine)", 医药工业 (PHARMACEUTICAL INDUSTRY), no. 6, 31 December 1975 (1975-12-31), DOI: 20200304154205X *

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