WO2020052629A1 - Application d'un ctpb activateur de p300 et d'un dérivé de celui-ci pour améliorer l'expression du collagène col17a1 - Google Patents

Application d'un ctpb activateur de p300 et d'un dérivé de celui-ci pour améliorer l'expression du collagène col17a1 Download PDF

Info

Publication number
WO2020052629A1
WO2020052629A1 PCT/CN2019/105587 CN2019105587W WO2020052629A1 WO 2020052629 A1 WO2020052629 A1 WO 2020052629A1 CN 2019105587 W CN2019105587 W CN 2019105587W WO 2020052629 A1 WO2020052629 A1 WO 2020052629A1
Authority
WO
WIPO (PCT)
Prior art keywords
ctpb
col17a1
activator
expression
hair
Prior art date
Application number
PCT/CN2019/105587
Other languages
English (en)
Chinese (zh)
Inventor
苏锦熙
Original Assignee
潘治忠
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 潘治忠 filed Critical 潘治忠
Publication of WO2020052629A1 publication Critical patent/WO2020052629A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia

Definitions

  • the present invention relates to the field of pharmaceuticals and toiletries, and more specifically, the present invention discloses the use of a CTPB activator.
  • Hair follicle stem cells promote hair follicle regeneration and hair growth, and also repair damaged epidermis.
  • the differentiation of hair follicle stem cells is regulated by a variety of pseudogenes, including enhancers and the marker histone H3 (H3K27Ac).
  • Enhancers are short DNA sequences that regulate the expression of a target gene. When the function of the enhancer is affected, it can lead to various diseases, such as autoimmune diseases and cancer.
  • enhancers such as ATAC-seq and immunoprecipitation combined with high-throughput sequencing chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq), which can find out how a fixed target is connected in the genome
  • Histone markers such as histone markers, transcription factors or co-acting factors.
  • H3K27ac active histone labeling H3K27ac or acetyltransferase p300 ChIP-seq, and ChIP-seq integrating multiple transcription factors.
  • SE Super-enhancer
  • SE has attracted much attention.
  • Super enhancers are a unique group of active enhancers. They are dense enhancers and have a particularly strong active histone marker H3K27ac.
  • H3K27ac active histone marker
  • the first object of the present invention is to provide a use of a p300 activator CTPB to increase the expression of collagen Col17A1, which is completed based on the following research by the inventors: by analyzing a variety of super-enhancers in cells, including immune cells , Cerebellum, cerebral cortex, heart, liver, spleen, thyroid, intestine, and hair follicle stem cells, the inventors found that the super enhancer that regulates the Col17A1 gene is a super enhancer specific to hair follicle stem cells, so it can be a target to observe How various compounds and pseudogenetic mechanisms regulate the expression of Col17A1 gene.
  • CTPB increased the expression of Col17A1 in a concentration gradient in fibroblasts, indicating that the apparent regulatory protein p300 is closely related to the differentiation of fibroblasts into hair follicle cells.
  • Hair loss began to occur in 20-month-old C57 mice, and was applied to the skin with p300 activator CTPB (apply daily at a concentration of 200 nM in PEG-400 / ethanol / water at a ratio of 40% / 20% / 40%), mice weighed 35g / one, and treated for 14 days), compared with the control group (PEG-400 / ethanol / water only, the ratio was 40% / 20% / 40%), CTPB could increase Col17A1 Express and improve dissection.
  • the above findings contributed to the present invention.
  • Enhancers / super-enhancers hundreds of super-enhancers control most of the key genes that confer properties and functions to each cell. Changes in cell identity may begin and end with these superenhancers, which are very powerful, but also extremely sensitive to environmental changes.
  • p300 is a member of the p300-CBP transcription coactivator family. It is involved in the transcriptional regulation of multiple transcription factors in different physiological processes, and has attracted much attention. Although P300 and CBP are encoded by different genes, their structures and functions are very similar, so p300 and CBP are classified into the same protein family. With a molecular weight of 300 kDa, p300 has a fairly high homology to CBP and is highly conserved among mammals. There are many functions of p300, including various physiological processes such as cell cycle regulation and cell differentiation. As a histone acetyltransferase (HAT), p300 can acetylate four core histones.
  • HAT histone acetyltransferase
  • p300 catalyzes the acetyl group in acetyl-CoA and transfers it to the ⁇ -amino group of the N-terminal lysine residue of histone, neutralizing the positive charge above and weakening the interaction between DNA and histone, thereby opening
  • the highly ordered chromatin structure facilitates the binding of transcription factors and RNA polymerase II to DNA, thereby facilitating transcription.
  • CTPB as a small molecule compound, is an activator of the p300-CBP protein family and acts on p300.
  • ECM extracellular matrix
  • Fibroblast fibroblasts are cells that synthesize extracellular matrix and collagen, and play an important role in animal wound healing.
  • the first object of the present invention is the use of the p300 activator CTPB to increase the expression of collagen Col17A1;
  • the use of the p300 activator CTPB in the preparation of a drug for treating hair loss is preferred.
  • the use of the p300 activator CTPB in the preparation of a medicament for promoting hair hyperplasia is preferred.
  • the molecular formula of CTPB of p300 activator is
  • Another object of the present invention is to disclose a preparation which is a solution containing CTPB, PEG-400, ethanol, and water, wherein the concentration of CTPB and its derivatives is 50 nM-4 ⁇ M.
  • the concentration of CTPB and its derivatives in the above formulation is 50 nM-4 ⁇ M.
  • a final object of the present invention is the use of the p300 activator CTPB in the preparation of hair restorers and / or treatments for hair loss.
  • CTPB is a p300 protein activator in the prior art, which can promote the proliferation of nerve cells to improve Parkinson's disease (PD).
  • the inventors of the present invention have found that CT300, a p300 activator, can increase the expression of collagen Col17A1.
  • collagen Col17A1 is digested by proteases, which promotes hair follicle stem cells to apoptosis, and at the same time enhances the inflammatory response, which eventually leads to hair loss. Histone acetylation is an important part of epigenetic research.
  • P300 regulates the transcriptional expression of genes by binding with acetylated lysine, and is a driving factor for hair follicle stem cell differentiation, while the small molecule compound CTPB is its activator.
  • CTPB small molecule compound for treating hair loss or promoting hair hyperplasia, which can be used for the early prevention and treatment of the disease. At the same time, it can also be used as a hair growth agent or hair loss treatment in shampoo products.
  • Figure 1 The results of the action of the super enhancer related to the Col17A1 gene on hair follicle stem cells, indicating that the super enhancer of COL17A1 is found only in hair follicle stem cells;
  • FIG. 3 is a comparison diagram of CTPB applied to the skin for treatment of hair loss or promotion of hair growth in Example 2;
  • Fig. 5 Example 2 qRT-PCR results of CTPB on Col17A1 expression level in skin of C57 mice at 20 months.
  • the mouse in the test example of the present invention is a C57BL / 6J mouse, which is from The Jackson Laboratory in the United States. Other raw materials are commercially available unless otherwise specified.
  • Example 1 The effect of CTPB (Santa Cruz, USA) on the expression of Col17A gene in fibroblast 10T1 / 2 was investigated.
  • the expression level of Col17A1 gene also decreases during skin aging in mice. The results are shown in Figure 2.
  • 10T 1/2 cells CCL-226, ATCC, USA
  • GAPDH is a universal internal reference, not a test 200nM CTPB increases the expression of Col17A1, and the effect of CTPB is positively related to its increase in Col17A1, indicating that CTPB plays an important role in 10T1 / 2 cells.
  • the reason for choosing CTPB for hair loss is super enhancement of p300 and Col17A1. Son is the target of treatment.
  • GAPDH is widely used as an internal reference for qRT-PCR cDNA standardization.
  • the target cDNA content of each sample is divided by the GAPDH content of this sample to obtain the relative content of the target cDNA of each sample. Compare. The same results are shown in Figure 4.
  • the qRT-PCR results showed that CTPB at 200nM and higher concentrations significantly increased the expression of Col17A1 after 16 hours, while CTPB increased the expression of Col17A1 in a gradient-dependent manner, of which 200nM inhibited JQ1. It is sufficiently significant that its role in activating p300 is positively correlated with Col17A1 expression, confirming the role of epigenetic regulatory protein p300 in 10T1 / 2 cells.
  • Example 2 The effect of exogenously added CTPB on treating hair loss or promoting hair hyperplasia was studied.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne une application d'un CTPB activateur de p300 et d'une préparation de celui-ci dans la préparation d'un régénérateur de cheveux et/ou d'un agent de traitement de la perte des cheveux et pour la préparation d'un médicament pour le traitement de la perte des cheveux/la stimulation de la régénération des cheveux.
PCT/CN2019/105587 2018-09-13 2019-09-12 Application d'un ctpb activateur de p300 et d'un dérivé de celui-ci pour améliorer l'expression du collagène col17a1 WO2020052629A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811068676.9A CN109045001A (zh) 2018-09-13 2018-09-13 p300活化剂CTPB及其衍生物在提高胶原蛋白Col17A1表达的用途
CN201811068676.9 2018-09-13

Publications (1)

Publication Number Publication Date
WO2020052629A1 true WO2020052629A1 (fr) 2020-03-19

Family

ID=64761437

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/105587 WO2020052629A1 (fr) 2018-09-13 2019-09-12 Application d'un ctpb activateur de p300 et d'un dérivé de celui-ci pour améliorer l'expression du collagène col17a1

Country Status (2)

Country Link
CN (1) CN109045001A (fr)
WO (1) WO2020052629A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109045001A (zh) * 2018-09-13 2018-12-21 潘治忠 p300活化剂CTPB及其衍生物在提高胶原蛋白Col17A1表达的用途
WO2020196801A1 (fr) * 2019-03-27 2020-10-01 国立大学法人 東京医科歯科大学 Composition pour la peau

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004053140A2 (fr) * 2002-12-12 2004-06-24 Jawaharlal Nehru Centre For Advanced Scientific Research Modulateurs (inhibiteurs/activateurs) d'histone acetyltransferases
US20070148228A1 (en) * 1999-02-22 2007-06-28 Merrion Research I Limited Solid oral dosage form containing an enhancer
US20070292512A1 (en) * 2006-06-09 2007-12-20 Merrion Research Ii Limited Solid Oral Dosage Form Containing an Enhancer
EP2982745A1 (fr) * 2014-08-06 2016-02-10 Johann Wolfgang Goethe-Universität, Frankfurt am Main Procédé d'expansion de cellules immunitaires
CN109045001A (zh) * 2018-09-13 2018-12-21 潘治忠 p300活化剂CTPB及其衍生物在提高胶原蛋白Col17A1表达的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070148228A1 (en) * 1999-02-22 2007-06-28 Merrion Research I Limited Solid oral dosage form containing an enhancer
WO2004053140A2 (fr) * 2002-12-12 2004-06-24 Jawaharlal Nehru Centre For Advanced Scientific Research Modulateurs (inhibiteurs/activateurs) d'histone acetyltransferases
US20070292512A1 (en) * 2006-06-09 2007-12-20 Merrion Research Ii Limited Solid Oral Dosage Form Containing an Enhancer
EP2982745A1 (fr) * 2014-08-06 2016-02-10 Johann Wolfgang Goethe-Universität, Frankfurt am Main Procédé d'expansion de cellules immunitaires
CN109045001A (zh) * 2018-09-13 2018-12-21 潘治忠 p300活化剂CTPB及其衍生物在提高胶原蛋白Col17A1表达的用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DEVIPRIYA B: "Charge density distribution and the electrostatic moments of CTPB in the active site of p300 enzyme: A DFT and charge density study", JOURNAL OF THEORETICAL BIOLOGY, 31 December 2013 (2013-12-31), XP028699767, ISSN: 0022-5193 *
KARANAM BALASUBRAMANYAM: "Small Molecule Modulators of Histone Acetyltransferase p300", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 21, 23 May 2003 (2003-05-23) - 31 December 2003 (2003-12-31), pages 19134 - 19140, XP008123444, ISSN: 0021-9258 *
MANTELINGU K: "Activation of p300 Histone Acetyltransferase by Small Mo- lecules Altering Enzyme Structure: Probed by Surface-Enhanced Raman Spectro- scopy", JOURNAL OF PHYSICAL CHEMISTRY B, vol. 111, no. 17, 7 April 2007 (2007-04-07) - 3 May 2007 (2007-05-03), pages 4527 - 4534, XP055075158, ISSN: 1520-6106 *

Also Published As

Publication number Publication date
CN109045001A (zh) 2018-12-21

Similar Documents

Publication Publication Date Title
AU744134B2 (en) Use of a drug capable of modulating the regulation of UPC-2 and method for screening for potential drugs against obesity
Zhang et al. Nobiletin protects against cerebral ischemia via activating the p-Akt, p-CREB, BDNF and Bcl-2 pathway and ameliorating BBB permeability in rat
Croce et al. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?
Zhao et al. Prophylactic neuroprotection against stroke: low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function
Benedetti et al. A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: a multimodal genetic imaging study
Liu et al. Emodin alleviates CCl4‑induced liver fibrosis by suppressing epithelial‑mesenchymal transition and transforming growth factor‑β1 in rats
Chen et al. Transcriptome sequencing provides insights into the mechanism of hypoxia adaption in bighead carp (Hypophthalmichthys nobilis)
Yadav et al. Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish
WO2020052629A1 (fr) Application d'un ctpb activateur de p300 et d'un dérivé de celui-ci pour améliorer l'expression du collagène col17a1
WO2022156026A1 (fr) Utilisation de lncrna xr_595534.2 dans la préparation d'un médicament pour le traitement ou la prévention de la douleur chronique
Zhu et al. Manual acupuncture relieves microglia-mediated neuroinflammation in a rat model of traumatic brain injury by inhibiting the RhoA/ROCK2 pathway
Fan et al. Alpinetin promotes hair regeneration via activating hair follicle stem cells
Chen et al. Promoting neurogenesis in hippocampal dentate gyrus of chronic unpredictable stress-induced depressive-like rats with paeoniflorin
Wang et al. Knockout of Sirt2 alleviates traumatic brain injury in mice
Li et al. Deletion of Mst1 attenuates neuronal loss and improves neurological impairment in a rat model of traumatic brain injury
Dai et al. Epigenetic modification of Kiss1 gene expression in the AVPV is essential for female reproductive aging
Yu et al. miR-141-3p protects against blood–brain barrier disruption and brain injury after intracerebral hemorrhage by targeting ZEB2
Liu et al. Downregulated Phosphoglycerate Kinase 1 Attenuates Cerebral Ischemia–Reperfusion Injury by Reversing Neuroinflammation and Oxidative Stress through the Nuclear Factor Erythroid 2 Related Factor 2/ARE Pathway
Ma et al. Recombinant human erythropoietin protects myocardial cells from apoptosis via the janus-activated kinase 2/signal transducer and activator of transcription 5 pathway in rats with epilepsy
Fang et al. Hirsutella sinensis fungus improves cardiac function in mouse model of heart failure
Luo et al. Calcitonin gene-related peptide downregulates expression of inducible nitride oxide synthase and caspase-3 after intestinal ischemia-reperfusion injury in rats
Hong et al. Integrative analysis identifies region-and sex-specific gene networks and Mef2c as a mediator of anxiety-like behavior
Xu et al. Integration of ATAC-Seq and RNA-Seq identifies key genes and pathways involved in the neuroprotection of S-adenosylmethionine against perioperative neurocognitive disorder
Zhao et al. In vitro effects of nerve growth factor on cardiac fibroblasts proliferation, cell cycle, migration, and myofibroblast transformation
Kramberger et al. Whole transcriptome expression array analysis of human colon fibroblasts culture treated with Helichrysum italicum supports its use in traditional medicine

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: 19860872

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19860872

Country of ref document: EP

Kind code of ref document: A1