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WO2022027237A1 - Application du quizartinib en guise d'inhibiteur de nécroptose - Google Patents

Application du quizartinib en guise d'inhibiteur de nécroptose Download PDF

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Publication number
WO2022027237A1
WO2022027237A1 PCT/CN2020/106841 CN2020106841W WO2022027237A1 WO 2022027237 A1 WO2022027237 A1 WO 2022027237A1 CN 2020106841 W CN2020106841 W CN 2020106841W WO 2022027237 A1 WO2022027237 A1 WO 2022027237A1
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WIPO (PCT)
Prior art keywords
quizatinib
application
inhibitor
disease
necroptosis
Prior art date
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Ceased
Application number
PCT/CN2020/106841
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English (en)
Chinese (zh)
Inventor
查运红
李敏
何小燕
魏钧
王君
余雅婕
胡昕倩
牟彦
祝国锋
赵海龙
黄明
张宏冰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
First People's Hospital Of Yichang People's Hospital Of China Three Gorges University
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First People's Hospital Of Yichang People's Hospital Of China Three Gorges University
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Application filed by First People's Hospital Of Yichang People's Hospital Of China Three Gorges University filed Critical First People's Hospital Of Yichang People's Hospital Of China Three Gorges University
Priority to PCT/CN2020/106841 priority Critical patent/WO2022027237A1/fr
Priority to CN202011002146.1A priority patent/CN112076198B/zh
Publication of WO2022027237A1 publication Critical patent/WO2022027237A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the application of quizatinib as a programmed necrosis inhibitor, and belongs to the technical field of medicine.
  • Cytokines were significantly elevated in both ICU and non-ICU patients, and some of these cytokines were more concentrated in critically ill ICU patients. Compared with ordinary patients with novel coronavirus pneumonia, the plasma levels of inflammatory cytokines IL-2, IL-7, IL-10, GSCF, IP10, MCP1, MIP1A and TNF ⁇ were higher in severe patients. Prevention and treatment of sepsis in patients with novel coronavirus pneumonia and inhibition of inflammatory cytokine storm are expected to improve the survival prognosis of patients with novel coronavirus pneumonia.
  • RIPK1 Activation of RIPK1 promotes the production of cytokines IL-6, IFN-g, MCP-1, IL-10, GSCF, and TNF ⁇ , which is consistent with a key feature of elevated proinflammatory cytokines in severe COVID-19 patients.
  • RIPK1 inhibitors are expected to prevent and treat sepsis in patients with novel coronavirus pneumonia, inhibit inflammatory cytokine storm, and improve the survival prognosis of patients with novel coronavirus pneumonia.
  • the technical problem to be solved by the present invention is to provide an application of quizatinib as a programmed necrosis inhibitor.
  • the technical scheme adopted in the present invention is:
  • the necroptosis initiation markers include the S166 site of RIPK1 and the S345 site of MLKL.
  • Diseases characterized by abnormal activation of programmed necrosis include COVID-19, pneumonia, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, pus Toxicosis, ischemic stroke, hemorrhagic stroke, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, and Duchenne muscle Malnutrition.
  • Necroptosis is a receptor-mediated, caspase-independent, highly regulated cell death process with typical necrotic morphological characteristics.
  • TNF- ⁇ tumor necrosis factor ⁇
  • RIPK1 receptor-interacting Protein kinase 1
  • RIPK3 receptor-interacting protein kinase 3
  • MLKL mixed-lineage kinase domain-like pseudokinase
  • TNF ⁇ +SM-164+zVAD can effectively induce the occurrence of programmed necrosis.
  • TSZ antitumor drug
  • Quizartinib AC220
  • TSZ-induced programmed necrosis and further verified at the molecular level that quizartinib rescues programmed necrosis by inhibiting RIPK1 activity.
  • the present invention proposes a new method for treating related diseases characterized by abnormal activation of programmed necrosis, aiming at the existing treatment bottleneck.
  • the present invention administers a sufficient amount of quizatinib (AC220) orally, thereby inhibiting the abnormal activation of programmed necrosis, relieving the clinical symptoms of such diseases, improving the prognosis of patients, and improving the quality of life of patients.
  • AC220 quizatinib
  • quizatinib can significantly inhibit RIPK1-dependent apoptosis and programmed necrosis.
  • quizatinib AC220
  • Fig. 1 is the accompanying drawing that quizatinib inhibits the programmed cell necrosis induced by T/S/Z in the present invention
  • Fig. 2 is the accompanying drawing of the safety and effectiveness of quizatinib in different cell lines in the present invention
  • Fig. 3 is the accompanying drawing that quizatinib can obviously inhibit the activation of programmed necrosis in the present invention
  • Fig. 4 is the accompanying drawing that quizatinib significantly improves the survival rate and body temperature of SIRS mice in the present invention
  • Fig. 5 is a drawing showing that quizatinib in the present invention significantly reduces lung inflammation in SIRS mice.
  • This example discloses the application of quizatinib as a programmed necrosis inhibitor.
  • the necroptosis initiation markers include the S166 site of RIPK1 and the S345 site of MLKL.
  • Diseases characterized by abnormal activation of programmed necrosis include COVID-19, pneumonia, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, pus Toxicosis, ischemic stroke, hemorrhagic stroke, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, and Duchenne muscle Malnutrition.
  • DMSO mouse hippocampal neuron cells
  • HT-29 human colon cancer cells
  • DMSO 200nM SM-164+20 ⁇ M zVAD(S/Z)
  • AC220 200nM SM-164+20 ⁇ M zVAD+500nM quizatinib
  • HT22 added 10ng/ml mTNF- ⁇
  • HT- 29 The programmed necrosis of cells was induced by adding 10ng/ml hTNF- ⁇ , and the number of surviving cells was detected by ATP assay.
  • T TNF ⁇
  • S SM164
  • Z zVAD
  • N Nec-1
  • Q Quizartinib.
  • the quizatinib group was compared with the model group (****P ⁇ 0.0001).
  • HT-29 cells pre-treated cells with different concentrations of quizatinib (AC220) + 200nM SM-164 + 20 ⁇ M zVAD for 30min, then add 10ng/ml hTNF- ⁇ to induce programmed necrosis, and use ATP assay to detect viable cells number.
  • FIG. 3 shows that quizatinib (AC220) can significantly inhibit the activation of programmed necrosis.
  • Three cell lines, L929, HT22, and RGC5 were treated with T/S/Z to induce programmed necrosis of cells. It could be clearly observed that the addition of quizatinib could significantly rescue the programmed cell necrosis induced by T/S/Z at 4 hours. .
  • Cell samples were collected at 0, 2, and 4 hours, and after protein extraction, Western blotting was performed.
  • the markers of programmed necrosis activation, p-RIPK1 (S166) and p-MLKL (S345) could be significantly inhibited, suggesting that quizatinib Programmed necrosis can be inhibited at the cellular level and cell death can be rescued.
  • the RIPK1-dependent cell death pathway is involved in TNF- ⁇ -induced systemic inflammatory response syndrome (SIRS).
  • SIRS mouse model was successfully established by injecting 5 ⁇ g of TNF ⁇ into the tail vein of 8-week-old C57BL/6 mice. Quizatinib (AC220) can significantly improve the hypothermic state of mice (****P ⁇ 0.0001) and improve the survival rate of mice (***P ⁇ 0.001). The specific results are shown in Table 4 and Table 5.
  • FIG 4 shows that quizatinib (AC220) can significantly improve the survival rate and body temperature of SIRS mice.
  • quizatinib can significantly improve the hypothermic state of mice (****P ⁇ 0.0001) and improve the survival rate of mice (*** P ⁇ 0.001).
  • the lung inflammation in mice was significantly reduced after administration.
  • related diseases characterized by abnormal activation of programmed necrosis such as pneumonia, new coronary pneumonia, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, etc.
  • programmed necrosis such as pneumonia, new coronary pneumonia, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, etc.
  • FIG. 5 shows that quizatinib (AC220) can significantly reduce lung inflammation in SIRS mice.
  • quizatinib AC220
  • a mouse model of systemic inflammatory response syndrome characterized by abnormal activation of programmed necrosis quizatinib was applied.
  • the Quizatinib can significantly reduce lung inflammation in mice and reduce inflammatory cell infiltration in the lungs of mice, suggesting that quizatinib can treat new coronary pneumonia.
  • the present invention can be used as a new treatment method for related diseases characterized by abnormal activation of programmed necrosis.
  • Related diseases characterized by abnormal activation of programmed necrosis such as amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, etc.
  • clinical treatment still has not achieved good results .
  • the purpose of the present invention is to propose a new method for treating related diseases characterized by abnormal activation of programmed necrosis, aiming at the existing treatment bottleneck.
  • the present invention is useful in related diseases (such as amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, etc.) characterized by abnormal activation of programmed necrosis.
  • related diseases such as amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, systemic inflammatory response syndrome, etc.
  • a sufficient amount of quizatinib (AC220) is administered orally to inhibit the abnormal activation of programmed necrosis, relieve the clinical symptoms of these diseases, and improve the prognosis and quality of life of patients.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Physical Education & Sports Medicine (AREA)
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  • Diabetes (AREA)
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Abstract

Une application du quizartinib en guise d'inhibiteur de nécroptose. L'invention concerne une application du quizartinib en guise d'inhibiteur de nécroptose cellulaire dépendant de RIPK1. L'invention concerne également une application du quizartinib en guise d'inhibiteur de la phosphorylation du marqueur d'initiation de nécroptose cellulaire, le marqueur d'initiation de nécroptose cellulaire comprenant un site S166 de RIPK1 et un site S345 de MLKL. L'invention concerne aussi une application du quizartinib en guise d'inhibiteur de nécroptose dans des maladies caractérisées par une activation anormale de la nécroptose, les maladies caractérisées par une activation anormale de la nécroptose incluant la COVID-19, la pneumonie, la sclérose latérale amyotrophique, la sclérose en plaques, la maladie intestinale inflammatoire, la maladie de Crohn, la lésion du type ischémie-reperfusion, le syndrome de réponse inflammatoire systémique, le sepsis, la thrombose artérielle cérébrale, l'accident vasculaire cérébral hémorragique, le psoriasis, la polyarthrite rhumatoïde et similaires. Une nouvelle méthode de traitement de maladies associées caractérisées par une activation anormale de la nécroptose est fournie pour des goulots d'étranglement de traitement existants.
PCT/CN2020/106841 2020-08-04 2020-08-04 Application du quizartinib en guise d'inhibiteur de nécroptose Ceased WO2022027237A1 (fr)

Priority Applications (2)

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PCT/CN2020/106841 WO2022027237A1 (fr) 2020-08-04 2020-08-04 Application du quizartinib en guise d'inhibiteur de nécroptose
CN202011002146.1A CN112076198B (zh) 2020-08-04 2020-09-22 奎扎替尼在制备治疗全身炎症反应综合征药物中的应用

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PCT/CN2020/106841 WO2022027237A1 (fr) 2020-08-04 2020-08-04 Application du quizartinib en guise d'inhibiteur de nécroptose

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022027237A1 (fr) * 2020-08-04 2022-02-10 宜昌市第一人民医院（三峡大学人民医院） Application du quizartinib en guise d'inhibiteur de nécroptose
CN116036283B (zh) * 2022-12-30 2025-09-02 中国科学院武汉病毒研究所 SARS-CoV-2和SFTSV病毒治疗的靶点及应用

Citations (4)

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CN103655575A (zh) * 2012-09-17 2014-03-26 杨育新 一类治疗创伤性脑损伤疾病的化合物及其用途
WO2016133194A1 (fr) * 2015-02-20 2016-08-25 第一三共株式会社 Polythérapie pour traiter un cancer
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CN112076198A (zh) * 2020-08-04 2020-12-15 宜昌市第一人民医院（三峡大学人民医院） 奎扎替尼作为程序性坏死抑制剂的应用

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CN103655575A (zh) * 2012-09-17 2014-03-26 杨育新 一类治疗创伤性脑损伤疾病的化合物及其用途
WO2016133194A1 (fr) * 2015-02-20 2016-08-25 第一三共株式会社 Polythérapie pour traiter un cancer
KR20180009034A (ko) * 2016-07-14 2018-01-25 중앙대학교 산학협력단 퀴잘티닙을 유효성분으로 포함하는 피임용 약학적 조성물
CN112076198A (zh) * 2020-08-04 2020-12-15 宜昌市第一人民医院（三峡大学人民医院） 奎扎替尼作为程序性坏死抑制剂的应用

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MARTENS SOFIE; HOFMANS SAM; DECLERCQ WIM; AUGUSTYNS KOEN; VANDENABEELE PETER: "Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs", TRENDS IN PHARMACOLOGICAL SCIENCES., ELSEVIER, HAYWARTH., GB, vol. 41, no. 3, 5 February 2020 (2020-02-05), GB , pages 209 - 224, XP086060785, ISSN: 0165-6147, DOI: 10.1016/j.tips.2020.01.002 *
SCHNETZKE ULF; FISCHER MIKE; SPIES-WEISSHART BÄRBEL; ZIRM ELISABETH; HOCHHAUS ANDREAS; MÜLLER JÖRG P.; SCHOLL SEBASTIAN : "The E3 ubiquitin ligase TRAF2 can contribute to TNF-α resistance in FLT3-ITD-positive AML c", LEUKEMIA RESEARCH, NEW YORK,NY, US, vol. 37, no. 11, 12 August 2013 (2013-08-12), US , pages 1557 - 1564, XP028760901, ISSN: 0145-2126, DOI: 10.1016/j.leukres.2013.08.004 *

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