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WO2025150553A1 - Agent thérapeutique contre la fibrose pulmonaire idiopathique - Google Patents

Agent thérapeutique contre la fibrose pulmonaire idiopathique

Info

Publication number
WO2025150553A1
WO2025150553A1 PCT/JP2025/000613 JP2025000613W WO2025150553A1 WO 2025150553 A1 WO2025150553 A1 WO 2025150553A1 JP 2025000613 W JP2025000613 W JP 2025000613W WO 2025150553 A1 WO2025150553 A1 WO 2025150553A1
Authority
WO
WIPO (PCT)
Prior art keywords
pulmonary fibrosis
ipf
pak2
idiopathic pulmonary
fibroblasts
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/JP2025/000613
Other languages
English (en)
Japanese (ja)
Inventor
雄 藤田
潤 荒屋
直昭 渡邊
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.)
Jikei University
Original Assignee
Jikei University
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 Jikei University filed Critical Jikei University
Publication of WO2025150553A1 publication Critical patent/WO2025150553A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for idiopathic pulmonary fibrosis.
  • Idiopathic pulmonary fibrosis is a chronic progressive interstitial lung disease of unknown cause characterized by intractable and progressive pulmonary fibrosis and a poor prognosis with a 5-year survival rate of approximately 20-40%.
  • IPF is caused by the excessive production of extracellular matrix by myofibroblasts induced by chronic inflammation and tissue injury, and it is known that the formation of immature fibroblast nests in particular is deeply involved in the pathology.
  • the persistent abnormal activation of pulmonary myofibroblasts is mediated by various proteins, including transforming growth factors (TGFs), platelet-derived growth factors, and fibroblast growth factors, and is a key event in the development and progression of IPF.
  • TGFs transforming growth factors
  • the IPF microenvironment is composed of highly heterogeneous cells that dynamically interact.
  • the constant interplay between fibrotic tissue and its microenvironment plays a key role in the development, progression and response to various therapies of fibrosis.
  • the areas between fibrotic tissue and morphologically normal lung usually contain fibroblasts of various sizes, called early fibroblastic foci (FF).
  • FF early fibroblastic foci
  • FFs are the main pathogenic lesions in IPF and are composed of activated fibroblasts and myofibroblasts, which are the main effector cells responsible for the dysregulated extracellular matrix (ECM) deposition in various fibrotic conditions. Consistent with the idea that fibrosis spreads from FFs to non-involved alveoli, these structures are the sites of myofibroblast accumulation during pathological ECM deposition. Indeed, a higher number of FFs is associated with worsening symptoms in IPF patients.
  • ECM extracellular matrix
  • Single-cell RNA sequencing is a novel tool to analyze IPF lung heterogeneity at the single-cell level and develop a comprehensive gene expression atlas, but it lacks spatial information of single cells, which is essential for a comprehensive understanding of IPF progression.
  • Regional tissue heterogeneity is a characteristic pathological feature of human lung fibrosis. Therefore, the development of sequencing techniques to determine cell type-specific spatial profiles is urgently needed.
  • digital spatial transcriptomic approaches can provide gene expression information with spatial resolution and help to gain a general understanding of tissue formation and disease pathogenesis. Therefore, the use of this methodology can help to understand IPF lung fibrosis in various conditions.
  • the present invention aims to utilize the above methodology to provide a therapeutic agent for idiopathic pulmonary fibrosis based on a new mechanism of action.
  • the present invention is as follows. [1] A therapeutic agent for idiopathic pulmonary fibrosis comprising a PAK inhibitor as an active ingredient. [2] A therapeutic agent for idiopathic pulmonary fibrosis comprising a PAK2 inhibitor as an active ingredient. [3] The therapeutic agent for idiopathic pulmonary fibrosis according to [1] or [2], which is intended for use in patients having WNT5A+ CTHRC1+ myofibroblasts in their lung tissue. [4] A composition for treating idiopathic pulmonary fibrosis, comprising the therapeutic agent for idiopathic pulmonary fibrosis according to [1] or [2] and a pharma- ceutically acceptable carrier.
  • a diagnostic agent for diagnosing idiopathic pulmonary fibrosis comprising: a primer set for amplifying at least one molecule selected from the group consisting of POSTN, THBS2, MMP11, CTHRC1, COL5A2, MMP14, MXRA5, ENC1, COL12A1, MMP7, COL8A1, ASPN, TGFBI, COL5A1, SPON2, COL7A1, ADAM12, CREB3L1, PMEPA1, and VCAN in a sample, and/or a probe that binds to the molecule or its amplification product, and an antibody that binds to the molecule.
  • a method for detecting a diagnostic marker for idiopathic pulmonary fibrosis comprising detecting the amount of at least one molecule selected from the group consisting of POSTN, THBS2, MMP11, CTHRC1, COL5A2, MMP14, MXRA5, ENC1, COL12A1, MMP7, COL8A1, ASPN, TGFBI, COL5A1, SPON2, COL7A1, ADAM12, CREB3L1, PMEPA1, and VCAN from a sample derived from a subject.
  • 1 is a violin plot showing the expression of selected marker genes in each cluster.
  • UMAP visualization of the scRNA-seq dataset in Figure 3 is classified according to whether it is derived from normal or IPF lungs.
  • 1 is a bar graph comparing the composition of lung interstitial cell types between healthy subjects and IPF patients. These are the results of pseudo-time developmental trajectory analysis predicting different interstitial cell differentiation trajectories between healthy individuals and IPF patients.
  • DF advanced fibrotic lesion
  • the bottom panel shows representative immunoblot analysis showing the amount of ⁇ -smooth muscle actin ( ⁇ -SMA), type I collagen, and ⁇ -actin in lung fibroblasts treated with FRAX486 (100 nM and 1,000 nM) and FRAX597 (100 nM and 1,000 nM) for 48 h in the presence of TGF- ⁇ 1 (2 ng/mL).
  • Pirfenidone (PFD) and nintedanib (NTD) were used as positive controls to inhibit myofibroblast differentiation.
  • Quantitative immunoblot analysis results showing the amounts of type I collagen and ⁇ -SMA.
  • FIG. 13 is a violin plot of Pak2 between bleomycin-induced and control lung fibroblasts. This shows the results of immunoblotting analysis confirming increased phosphorylation of PAK2 in lung tissue of a BLM-induced fibrosis model. Graph showing the change in body weight observed following bleomycin administration. Body weight on day 0 before the start of treatment was set at 100. Values shown represent mean ⁇ SEM. **P ⁇ 0.01.
  • the present invention provides a therapeutic agent for idiopathic pulmonary fibrosis comprising a PAK inhibitor as an active ingredient.
  • PAK p21-activated kinase
  • PAK-6 PAK isoforms
  • PAK1 is essential for the growth of solid tumors, and overactivation or overexpression of PAK1 is known to cause diseases such as cancer, hypertension, diabetes, and Alzheimer's disease.
  • PAK1 The amino acid sequence of PAK1 is, for human PAK1, the sequence registered under GenBank accession number AAA65441.
  • the gene sequence of PAK1 is, for human PAK1, the sequence registered under GenBank accession number U24152.
  • Small molecule compounds that inhibit the kinase activity of PAK1 include IPA-3 (1,1'-dithiodi-2-naphthol), AG-1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine), FRAX597 (6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one), and FRAX4.
  • IPA-3 is a small molecule allosteric inhibitor of PAK1.
  • PAK2 The amino acid sequence of PAK2 is, for human PAK2, the sequence registered under GenBank accession number AAA65442.
  • the gene sequence of PAK2 is, for human PAK2, the sequence registered under GenBank accession number U24153.
  • PAK2 inhibitors are substances that inhibit signal transduction by PAK2, and are not limited as long as they inhibit the associated signal transduction pathway, and examples of such inhibitors include nucleic acids, proteins, and low molecular weight compounds. Examples of substances that act directly on PAK2 include low molecular weight compounds, proteins, antibodies, and aptamers. Examples of substances that suppress the expression of the gene encoding PAK2 include siRNA and antisense oligonucleotides.
  • Small molecule compounds that inhibit the kinase activity of PAK2 include FRAX486 (6-(2,4-dichlorophenyl)-8-ethyl-2-[[3-fluoro-4-(1-piperazinyl)phenyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one), FRAX597 (6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one), FRAX1036, and PF-3758309 ((S)-N-(2-(dimethylamino)-1-phenylethyl)-6,6-dimethyl-3-((2-methylthieno[3,2-d]pyrimidin-4-yl).
  • the PAK inhibitor used in the idiopathic pulmonary fibrosis treatment agent of this embodiment may be a pan-PAK inhibitor, but is preferably a PAK2 selective inhibitor.
  • the PAK inhibitor may be used in the form of a free form or in the form of a pharma- ceutically acceptable salt. It may also be used in the form of a solvate of the free form or in the form of a solvate of the salt.
  • the salts are not particularly limited as long as they are pharma- ceutically acceptable salts, and examples thereof include hydrochlorides, sulfates, hydrobromides, hydroiodides, phosphates, nitrates, benzoates, methanesulfonates, 2-hydroxyethanesulfonates, p-toluenesulfonates, acetates, propanoates, oxalates, malonates, succinates, glutarates, adipates, tartrates, maleates, fumarates, malates, mandelates, etc.
  • the solvates are not particularly limited as long as they are pharma-ceutically acceptable solvates, and examples thereof include hydrates, organic solvates, etc.
  • composition for treating idiopathic pulmonary fibrosis of this embodiment can be administered orally in the form of, for example, tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc., or parenterally in the form of inhalants, injections, suppositories, topical skin preparations, etc.
  • the composition for treating idiopathic pulmonary fibrosis of this embodiment may further contain additives.
  • additives include lubricants such as calcium stearate and magnesium stearate; sweeteners such as sucrose, lactose, saccharin and maltitol; flavorings such as peppermint and saffron oil; stabilizers such as benzyl alcohol and phenol; buffers such as phosphates and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; preservatives, etc.
  • the additives may be used alone or in combination of two or more.
  • the method of administration of the therapeutic agent for idiopathic pulmonary fibrosis or the composition for treating idiopathic pulmonary fibrosis is not particularly limited, and may be appropriately determined according to the symptoms, body weight, age, sex, etc. of the patient.
  • tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc. are orally administered.
  • Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and further administered intraarterially, intramuscularly, intradermally, subcutaneously, or intraperitoneally as necessary.
  • Suppositories are administered rectally. External preparations for skin are applied, attached, or sprayed to the affected area.
  • Inhalants are administered using devices such as nebulizers, metered dose inhalers, and dry powder inhalers.
  • the present invention provides a method for treating idiopathic pulmonary fibrosis, comprising administering to a patient in need of treatment an effective amount of a PAK inhibitor, a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • the present invention provides use of a PAK inhibitor, a pharma- ceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic agent for idiopathic pulmonary fibrosis or a composition for the treatment of idiopathic pulmonary fibrosis.
  • FF spots To characterize the cellular and molecular features of FF, we histologically identified them on H&E images (see Figure 2), and the Visium spots overlapping these areas were designated as FF spots. The accuracy of these FF spot selections was further verified by examining the spatial distribution of known FF markers, such as COL1A1, POSTN, and CTHRC1, on each Visium section.
  • IPF lung tissues show heterogeneous patterns of fibrosis as well as DF regions representing fibrotic remodeling, where mature scar tissue disrupts normal lung architecture and impairs gas exchange. Comparing FF and DF is important for understanding the dynamic progression of fibrosis and identifying therapeutic targets for both active fibrosis and its transition to fibrotic remodeling.
  • FF regions were mainly populated by CTHRC1+ fibroblasts, proliferative fibroblasts, and aberrant basaloids, whereas DF regions, unlike SMC/pericyte regions, had a higher cell proportion of WNT5A+ CTHRC1+ myofibroblasts, further supporting the idea that the transition to WNT5A+ CTHRC1+ myofibroblasts may be partially involved in the mechanism of FF to DF transition (see Figure 11).
  • Aberrant basaloids showed high levels of cell-cell interactions with both WNT5A+ CTHRC1+ myofibroblasts and CTHRC1+ fibroblasts, suggesting the existence of a profibrotic loop that promotes fibrosis progression.
  • FF index-high fibroblasts were also detected in control lung samples, the amount of FF index-high fibroblasts was higher in IPF samples. Spatially, the FF index effectively visualized fibroblast foci in IPF lung sections (see Figure 12).
  • PAK2 As part of the search for novel therapeutic targets, we focused on PAK2 because it is highly expressed in pathogenic CTHRC1+ fibroblasts and WNT5A+ CTHRC1+ myofibroblasts (see Figure 15) and small molecule inhibitors targeting PAK2 are available.
  • PAK2 PAK target gene set based on previously reported RNA-seq data.
  • the average expression level of the PAK target signature in each single cell was calculated using the module score algorithm and visualized with UMAP (see Figure 16).
  • the distribution of cells expressing high PAK target signature was very similar to that of cells with high FF index (see Figure 17), suggesting that PAK target genes are mainly expressed in profibrotic fibroblasts.
  • the expression of PAK2 was significantly higher in fibroblasts with high FF index than in fibroblasts with low FF index (see Figure 18).
  • PAK2 may be a potential therapeutic target for IPF by regulating the activity of pathogenic fibroblasts.
  • FRAX486 was administered intraperitoneally to evaluate its therapeutic potential on day 7 after BLM treatment, which corresponds to the onset of fibrotic conditions (see FIG. 29).
  • FIG. 32 severe weight loss was observed in BLM-treated mice compared to the weight loss observed in control mice.
  • treatment with FRAX486 restored body weight in BLM-induced mice, with levels at day 21 comparable to those in control mice.

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

Abstract

Cet agent thérapeutique contre la fibrose pulmonaire idiopathique contient un inhibiteur de PAK en tant que principe actif.
PCT/JP2025/000613 2024-01-11 2025-01-10 Agent thérapeutique contre la fibrose pulmonaire idiopathique Pending WO2025150553A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2024002318 2024-01-11
JP2024-002318 2024-01-11

Publications (1)

Publication Number Publication Date
WO2025150553A1 true WO2025150553A1 (fr) 2025-07-17

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ID=96387068

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WO (1) WO2025150553A1 (fr)

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MOELLER, A. ASK, K. WARBURTON, D. GAULDIE, J. KOLB, M.: "The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?", INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 40, no. 3, 1 January 2008 (2008-01-01), AMSTERDAM, NL, pages 362 - 382, XP022486808, ISSN: 1357-2725, DOI: 10.1016/j.biocel.2007.08.011 *
NEWMAN DONNA R., SILLS W. SHANE, HANRAHAN KATHERINE, ZIEGLER AMANDA, TIDD KATHLEEN MCGINNIS, COOK ELIZABETH, SANNES PHILIP L.: "Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts", JOURNAL OF HISTOCHEMISTRY AND CYTOCHEMISTRY, HISTOCHEMICAL SOCIETY, NEW YORK, NY, US, vol. 64, no. 2, 1 February 2016 (2016-02-01), US , pages 99 - 111, XP093335602, ISSN: 0022-1554, DOI: 10.1369/0022155415617988 *
TSUKUI TATSUYA, SUN KAI-HUI, WETTER JOSEPH B., WILSON-KANAMORI JOHN R., HAZELWOOD LISA A., HENDERSON NEIL C., ADAMS TAYLOR S., SCH: "Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis", NATURE COMMUNICATIONS, NATURE PUBLISHING GROUP, UK, vol. 11, no. 1, UK, pages 1 - 16, XP093335606, ISSN: 2041-1723, DOI: 10.1038/s41467-020-15647-5 *
YU HUAJUN, ZHANG ZHAO, HUANG HUI, WANG YAJUN, LIN BIYUN, WU SHANG, MA JINGYAO, CHEN BAOAN, HE ZHAN, WU JUN, ZHAO ZUGUO, ZHANG HAIT: "Inhibition of bleomycin-induced pulmonary fibrosis in mice by the novel peptide EZY-1 purified from Eucheuma", FOOD & FUNCTION, R S C PUBLICATIONS, GB, vol. 10, no. 6, 19 June 2019 (2019-06-19), GB , pages 3198 - 3208, XP093335171, ISSN: 2042-6496, DOI: 10.1039/C9FO00308H *

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