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WO2009033284A1 - Inhibiteurs de biosynthèse de collagène en tant qu'agents anti-tumeur - Google Patents

Inhibiteurs de biosynthèse de collagène en tant qu'agents anti-tumeur Download PDF

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Publication number
WO2009033284A1
WO2009033284A1 PCT/CA2008/001614 CA2008001614W WO2009033284A1 WO 2009033284 A1 WO2009033284 A1 WO 2009033284A1 CA 2008001614 W CA2008001614 W CA 2008001614W WO 2009033284 A1 WO2009033284 A1 WO 2009033284A1
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Prior art keywords
tumor
carcinoma
hsp47
inhibitor
injection
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PCT/CA2008/001614
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English (en)
Inventor
Brian Lichty
Vettai Ananthanarayanan
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Mcmaster University
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Publication of WO2009033284A1 publication Critical patent/WO2009033284A1/fr

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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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 present invention relates to an antitumor agent and methods of using the agent to prevent or treat a tumor.
  • agents and methods that interfere with collagen synthesis are provided.
  • Hsp47 is a collagen-specific chaperone that binds to nascent procollagen polypeptide strands as they transit through the ER and enter the Golgi apparatus. In the low-pH environment of the Golgi, Hsp47 dissociates from the now triple-helical procollagen molecule Procollagen polymerizes into dense aggregates s in the Golgi (Lamande and Bateman, 1999) before its secretion into the extracellular matrix where mature collagen is produced by higher order assembly and cross-linking (Bateman J. F., Lamande S. R., Ramshaw JAM. (1996).
  • Hsp47 is critical to proper collagen synthesis.
  • the absence of Hsp47 leads to premature polymerization of collagen fibrils in the ER and this leads to a stress response that induces apoptosis and the subsequent death of the cell (Marutani et al., 2004).
  • inhibition of Hsp47 function in cells expressing collagen leads to aberrant collagen secretion and can lead to the death of the secreting cell.
  • the present invention addresses the need for new cancer therapies based on inhibition of collagen formation.
  • the invention comprises strategies that target Hsp47 function to treat cancer.
  • the invention relates to various strategies to target Hsp47 expression and/or function within tumours to impair the growth of the tumour or to kill tumorous cells.
  • the invention encompasses methods and compositions that can be directed to both malignant cells and supporting tumour stroma.
  • compositions comprising agents that inhibit Hsp47 are provided.
  • the compositions are preferably used for the treatment of cancer.
  • a small molecule inhibitor of Hsp47 function is used to impair tumour growth. Collagen secreting cells within the tumour are targeted. This leads to impaired function of these cells and as a consequence, to cell death.
  • the inhibitor has a structure selected from the following formulae:
  • Ri is amine or substituted amine
  • R 2 is nitro
  • R3 is alkyloxy or halogen
  • R-i is halogen and R 2 is alkylcarboxylate.
  • the inhibitor is selected from the group consisting of:
  • the compound is compound 1 (also known as RF03420).
  • Hsp47 function In another aspect of the invention, methods for inhibiting Hsp47 function are provided. By inhibiting the function of this protein one can impair collagen production within a growing tumour and impede tumour growth and/or kill cells within a tumourous mass or metastases.
  • Potential target cells are any cells expressing Hsp47 and secreting collagen.
  • the tumor is selected from the group consisting of lung carcinoma, breast carcinoma, prostate carcinoma, colon adenocarcinoma, cervical carcinoma, endometrial carcinoma, ovarian carcinoma, bladder carcinoma, Wilm's tumor, fibrosarcoma, osteosarcoma, melanoma, synovial sarcoma, epidermoid carcinoma, pancreatic carcinoma, endocrine system carcinoma, astrocytoma, oligodendroglioma, menigioma, neuroblastoma, glioblastoma, ependyoma, Schwannoma, neurofibrosarcoma, neuroblastoma, and medullablastoma.
  • the target cells are malignant cells expressing Hsp47 and collagen.
  • the target cells are malignant stromal fibroblasts expressing Hsp47 and collagen.
  • these target cells are m endothelial cells expressing Hsp47 and collagen.
  • FIGURE 1 illustrates relative Hsp47 expression levels for several cell lines
  • FIGURE 2 shows graphically the viability of cultured cells following exposure to an Hsp47 inhibitor
  • FIGURE 3 illustrates the effect of topical treatment with an Hsp47 inhibitor on subcutaneous CT26 tumours
  • FIGURE 4 demonstrates systemic treatment of breast carcinoma in a xenograft model
  • FIGURE 5 illustrates the effect of peri-tumoural treatment in a subcutaneous colon cancer model
  • FIGURE 6 is a series of photomicrographs showing immunohistochemical staining of CT26 tumours
  • FIGURE 7 is a series of photomicrographs at a higher magnification illustrating immunohistochemical staining of Hsp47on CT26 tumours
  • FIGURE 8 illustrates immunohistochemical staining of normal tissues
  • FIGURE 9 illustrates immunohistochemical staining of MDA MB 231 tumours
  • Collagen synthesis is associated with solid tumour growth. Proper collagen synthesis and secretion requires Hsp47 function. By inhibiting Hsp47 function one can impair collagen synthesis and impair tumour growth. Inhibition of Hsp47 function in collagen secreting cells is very stressful to these cells and can kill them. In a growing tumour, collagen secretion can be mediated by malignant cells, normal stromal cells or both. Inhibition of Hsp47 function in these cells can inhibit tumour growth and/or kill the cells leading to tumour destruction.
  • the terms "inhibition of Hsp47 function” and "Hsp47 inhibitor” are used herein to refer to methods and compositions that inhibit Hsp47 expression, function and/or interaction with collagen.
  • Hsp47 is a novel therapeutic target for the treatment of cancer.
  • a method of treating a tumor by administering a composition comprising a Hsp47 inhibitor is provided.
  • Hsp47 inhibitors such as a small molecule, siRNA, shRNA, intrabody, antibody and peptide are encompassed.
  • the Hsp47 inhibitor may be administered in combination with other therapeutic agents, either at the same time or sequentially.
  • the additional therapeutic agent may be a chemotherapeutic agent.
  • additional agents include regulators of the unfolded protein response (UPR), endoplasmic reticulum-associated protein destruction (ERAD) response, the proteasome and heatshock protein function and combinations thereof.
  • UTR unfolded protein response
  • ESD endoplasmic reticulum-associated protein destruction
  • Compositions comprising a Hsp47 inhibitor are provided.
  • a composition comprising an inhibitor and an additional anti-tumor agent are encompassed.
  • compositions comprising together or sequentially an oncolytic virus and/or an anti-tumor pharmaceutical and methods for their use are also encompassed.
  • tumors including but not limited to, lung carcinoma, breast carcinoma, prostate carcinoma, colon adenocarcinoma, cervical carcinoma, endometrial carcinoma, ovarian carcinoma, bladder carcinoma, Wilm's tumor, fibrosarcoma, osteosarcoma, melanoma, synovial sarcoma, epidermoid carcinoma, pancreatic carcinoma, endocrine system carcinoma, astrocytoma, oligodendroglioma, menigioma, neuroblastoma, glioblastoma, ependyoma, Schwannoma, neurofibrosarcoma, neuroblastoma, and medullablastoma can be treated using the compositions and methods of the invention.
  • composition comprising the Hsp47 inhibitor may be administered via parenteral, oral, rectal, vaginal, topical, intranasal, inhalation, buccal, or ophthalmic administration.
  • the administration may be via intravenous injection, subcutaneous injection, intraperitoneal injection, intra-arterial injection, intramuscular injection, intralesional injection into the tumor, intralesional injection adjacent to the tumor, intravenous infusion, and/or intra-arterial infusion.
  • the route of administration and the dosage to be administered can be determined based on the type of tumor being treated and patient characteristics, such as weight, age, sex, etc.
  • FIG. 1 illustrates that tumour cells can express high levels of Hsp47 in some cases and Figures 6 and 7 demonstrate that tumour stromal fibroblasts can also express high levels in vivo.
  • two types of tumours can be targeted by agents that inhibit Hsp47 activity: Firstly, tumours where the malignant cells themselves are high expressors of collagen and Hsp47 can be targeted. This is exemplified by, but not limited to, breast carcinoma as demonstrated by the results using human breast carcinoma cell line MDA MB 231. In addition, tumours that induce a strong fibrotic response can be targeted.
  • Hsp47 inhibitor compounds identified have a high potential for arresting fibrosis.
  • the Hsp47 inhibitor compounds were tested for their ability to inhibit collagen production in several cell lines. Cell lines that express Hsp47 are more sensitive to inhibitor compounds, than a cell line that does not express Hsp47. While the human neuronal cell line HEK 293, and its derivatives such as 293T, do not express collagen or Hsp47, a number of other tumour cell lines do. As illustrated in Figure 1 , when treated with the Hsp47 inhibitor RF03420, the growth of cells expressing Hsp47 was inhibited to a greater degree than were the 293T cells. 293T cells do not express the target protein as shown in Figure 2.
  • the Hsp47 inhibitor, RF03420 was shown to inhibit tumour growth in vivo in a syngeneic colon carcinoma model when applied topically as shown in Figure 3 and when applied peritumourally as shown in Figure 5.
  • this compound was shown to inhibit tumour growth in a breast carcinoma xenograft model when delivered systemically as illustrated in Figure 4.
  • the highest expression of Hsp47 within the colon carcinoma model was seen in stromal fibroblasts near the surface of the tumour mass. Weaker expression was seen within the tumour cells themselves as shown in Figure 6 and 7.
  • Figure 8 illustrates normal, tumour-free tissues from an adult mouse display undetectable expression of Hsp47.
  • the fluorescent intensity was determined using LiCor software and plotted as relative to the GAPDH signal for each cell line. The results are shown in Figure 1 for the following cell lines: 293T (human neuronal), MDA-MB- 231 (human breast carcinoma), U2OS (human osteosarcoma), L929 (murine fibroblast), CT26 (murine colon carcinoma), B16 (murine melanoma).
  • Balb/c mice were engrafted with 1x10 6 CT26 subcutaneously.
  • Compound 1 RF03420, 250 ⁇ M in DMSO, 5 mice
  • Compound 2 RH01393, 250 ⁇ M in DMSO, 5 mice
  • DMSO DMSO 4 mice
  • the DMSO solutions were applied topically by painting the surface of the tumours with a small paintbrush. Treatment was continued until the tumour volume endpoint was reached as per institution prescribed animal utilization protocol. The results are shown in Figure 3. Two RF03420 treated mice were long-term survivors.
  • Example 4 Systemic Treatment of Breast Carcinoma in a Xenograft Model.
  • mice were engrafted with 2x10 6 MDA-MB231 subcutaneously. Seven days post engraftment treatment was started consisting of daily intraperitoneal injections of HSP47 inhibitor or vehicle. ⁇ O ⁇ l of 12mM Compound 1 (RF03420) in DMSO was diluted to 10Oul with DMSO and then this was mixed with 30OuI of saline just prior to injection (5 mice). 14ml of 7OmM Compound 2 (RH01393) in DMSO was diluted to 100 ⁇ l of DMSO and the mixed with 300 ml of saline for injection (4 mice).
  • the DMSO group received 100 ⁇ l of DMSO mixed with 300 ⁇ l of saline (5 mice). Mice were monitored and euthanized once endpoint was reached as per our animal use protocol. The results are shown in Figure 4 as A) Tumour volumes on last day of treatment and B) Survival proportions.
  • Example 5 Peri-tumoural Treatment in a Subcutaneous Colon Cancer Model.
  • mice were engrafted with 8x10 5 CT26 cells subcutaneously. Five days post engraftment treatment began with daily peritumoural subcutaneous injections of 100 ⁇ M HSP47 inhibitor (RF03420, 5 mice) in 1%DMSO or with vehicle (4 mice). Mice were monitored and euthanized once endpoint was reached as per our animal use protocol. The results are shown in Figure 5 as A) Tumour volumes and B) survival curves were recorded.
  • CT26 Tumours were removed from BaIb-C mice, fixed in 10% formalin (Sigma) for 72-90 hours at 4°C, paraffin embedded and sectioned at 4 ⁇ m.
  • Antigen retrieval was performed on the tissue using citrate buffer, pH 6.0 and then stained with OC-HSP47 monoclonal antibody (Stressgen) at a dilution of 1 :1000 using an ARK kit as per the manufacturers protocol (DAKO) and counterstained with hematoxalin/eosin (H&E).
  • Example 7 Higher Magnification of HSP47 lmmunohistochemical Staining of CT26 tumours.
  • Example 8 lmmunohistochemical Staining of Normal Tissues.
  • Example 9 lmmunohistochemical staining of MDA MB 231 Tumours.
  • MDA MB 231 tumours were removed from RAG2 -/- gamma chain -/- mice, fixed in 10% formalin (Sigma) for 72-90 hours at 4°C, paraffin embedded and sectioned at 4 ⁇ m.
  • Antigen retrieval was performed on the tissue using citrate buffer, pH 6.0 and then stained with ⁇ -HSP47 monoclonal antibody (Stressgen) at a dilution of 1 :1000 using an ARK kit as per the manufacturers protocol (DAKO) and counterstained with hematoxalin/eosin (H&E).
  • Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.
  • Stroma tumor agonist or antagonist. Cell cycle (Georgetown, Tex 4, 1022-1025.
  • Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(1) chains of type I procollagen.
  • Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay. Journal of cell science 120, 512-519.
  • Hsp47 and cyclophilin B traverse the endoplasmic reticulum with procollagen into pre-Golgi intermediate vesicles.

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Abstract

La présente invention concerne un procédé de traitement du cancer par l'inhibition de la formation de collagène. L'invention concerne en particulier de petites molécules qui inhibent l'activité Hsp47 et sont utilisées pour inhiber la prolifération de cellules tumorales ou pour tuer des cellules tumorales.
PCT/CA2008/001614 2007-09-14 2008-09-12 Inhibiteurs de biosynthèse de collagène en tant qu'agents anti-tumeur WO2009033284A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013119931A1 (fr) * 2012-02-10 2013-08-15 The Board Of Regents Of The University Of Texas System Modulateurs de protéines d'échange directement activées par l'ampc (epac)
CN103430026A (zh) * 2011-02-10 2013-12-04 国立大学法人长崎大学 急性肺损伤的诊断方法
CN104374918A (zh) * 2013-08-17 2015-02-25 复旦大学 热休克蛋白47胶质瘤相关肿瘤抗原及应用
WO2016106403A2 (fr) 2014-12-26 2016-06-30 Nitto Denko Corporation Compositions thérapeutiques et méthodes destinées à traiter les tumeurs malignes à l'aide de molécules d'arni ciblant hsp47 et p21
US9737512B2 (en) 2015-03-11 2017-08-22 The Board Of Regents Of The University Of Texas System Methods and compositions for treating chronic pain
WO2017170860A1 (fr) * 2016-03-30 2017-10-05 東レ株式会社 Inhibiteur de la protéine 47 de choc thermique
CN110437156A (zh) * 2019-08-26 2019-11-12 桂林医学院 丹皮酚二氢嘧啶酮类衍生物及其制备方法和应用
WO2020040185A1 (fr) * 2018-08-22 2020-02-27 日東電工株式会社 Médicament mettant en œuvre un inhibiteur de hsp47 pour augmenter la sensibilité à un médicament chimiothérapeutique
CN112739381A (zh) * 2018-08-22 2021-04-30 日东电工株式会社 使用了hsp47的抑制物质的癌转移抑制
US11045488B2 (en) 2014-12-26 2021-06-29 Nitto Denko Corporation RNA interference agents for GST-π gene modulation

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Cited By (21)

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Publication number Priority date Publication date Assignee Title
CN103430026A (zh) * 2011-02-10 2013-12-04 国立大学法人长崎大学 急性肺损伤的诊断方法
US9539256B2 (en) 2012-02-10 2017-01-10 The Board Of Regents Of The University Of Texas System Modulators of exchange proteins directly activated by cAMP (EPACS)
WO2013119931A1 (fr) * 2012-02-10 2013-08-15 The Board Of Regents Of The University Of Texas System Modulateurs de protéines d'échange directement activées par l'ampc (epac)
CN104374918A (zh) * 2013-08-17 2015-02-25 复旦大学 热休克蛋白47胶质瘤相关肿瘤抗原及应用
CN108024961A (zh) * 2014-12-26 2018-05-11 日东电工株式会社 使用靶向Hsp47和p21的RNAi分子的恶性肿瘤治疗组合物和方法
US11045488B2 (en) 2014-12-26 2021-06-29 Nitto Denko Corporation RNA interference agents for GST-π gene modulation
US9695206B2 (en) 2014-12-26 2017-07-04 Nitto Denko Corporation RNA interference agents for P21 gene modulation
US9771582B2 (en) 2014-12-26 2017-09-26 Nitto Denko Corporation RNA interference compositions and methods for malignant tumors
WO2016106403A3 (fr) * 2014-12-26 2016-08-18 Nitto Denko Corporation Compositions thérapeutiques et méthodes destinées à traiter les tumeurs malignes à l'aide de molécules d'arni ciblant hsp47 et p21
WO2016106403A2 (fr) 2014-12-26 2016-06-30 Nitto Denko Corporation Compositions thérapeutiques et méthodes destinées à traiter les tumeurs malignes à l'aide de molécules d'arni ciblant hsp47 et p21
US10023597B2 (en) 2014-12-26 2018-07-17 Nitto Denko Corporation RNA interference agents for p21 gene modulation
US10405749B2 (en) 2014-12-26 2019-09-10 Nitto Denko Corporation RNA agents for P21 gene modulation
USRE49431E1 (en) 2014-12-26 2023-02-28 Nitto Denko Corporation RNA interference agents for GST-PI gene modulation
USRE48887E1 (en) 2014-12-26 2022-01-11 Nitto Denko Corporation RNA interference compositions and methods for malignant tumors
US9737512B2 (en) 2015-03-11 2017-08-22 The Board Of Regents Of The University Of Texas System Methods and compositions for treating chronic pain
WO2017170860A1 (fr) * 2016-03-30 2017-10-05 東レ株式会社 Inhibiteur de la protéine 47 de choc thermique
CN112739381A (zh) * 2018-08-22 2021-04-30 日东电工株式会社 使用了hsp47的抑制物质的癌转移抑制
WO2020040185A1 (fr) * 2018-08-22 2020-02-27 日東電工株式会社 Médicament mettant en œuvre un inhibiteur de hsp47 pour augmenter la sensibilité à un médicament chimiothérapeutique
EP3851125A4 (fr) * 2018-08-22 2022-08-17 Nitto Denko Corporation Médicament mettant en oeuvre un inhibiteur de hsp47 pour supprimer les métastases
CN110437156B (zh) * 2019-08-26 2022-07-19 桂林医学院 丹皮酚二氢嘧啶酮类衍生物及其制备方法和应用
CN110437156A (zh) * 2019-08-26 2019-11-12 桂林医学院 丹皮酚二氢嘧啶酮类衍生物及其制备方法和应用

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