EP1003492A2 - Inhibitors of nf-kappab as activators of hsf and inducers of heat shock proteins - Google Patents

Inhibitors of nf-kappab as activators of hsf and inducers of heat shock proteins

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Publication number
EP1003492A2
EP1003492A2 EP98940106A EP98940106A EP1003492A2 EP 1003492 A2 EP1003492 A2 EP 1003492A2 EP 98940106 A EP98940106 A EP 98940106A EP 98940106 A EP98940106 A EP 98940106A EP 1003492 A2 EP1003492 A2 EP 1003492A2
Authority
EP
European Patent Office
Prior art keywords
hsf
inhibitors
pharmaceutically acceptable
acceptable derivatives
mixtures
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.)
Withdrawn
Application number
EP98940106A
Other languages
German (de)
English (en)
French (fr)
Inventor
Maria Gabriella Santoro
Antonio Rossi
Giuliano Elia
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.)
Consiglio Nazionale delle Richerche CNR
Original Assignee
Consiglio Nazionale delle Richerche CNR
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 Consiglio Nazionale delle Richerche CNR filed Critical Consiglio Nazionale delle Richerche CNR
Publication of EP1003492A2 publication Critical patent/EP1003492A2/en
Withdrawn legal-status Critical Current

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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
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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 inhibitors of the NF-/VB factor as activators of HSF and iducers of heat shock proteins. Particularly, the invention refers to said inhibitors as activators of HSF with anti-inflammatory, anti-proliferative, immuno-suppressive, cytoprotective and antiviral activity.
  • NF-/VB Nuclear Factor - kappaB or Nuclear Factor - KB
  • NF-/VB Nuclear Factor - kappaB or Nuclear Factor - KB
  • NF-VB is activated in response to different stimuli, among which inflammatory cytokines, UV radiation, bacterial and viral infections. Stimulation triggers the release of NF-VB from 1/cB in consequence of the phosphorylation and the following degradation of the 1/ B-alpha protein (P.A. Baeuerle and T. Henkel,
  • NF-/ B translocates to the nucleus where it binds to DNA at specific / B-sites and induces the transcription of a variety of genes encoding proteins involved in controlling the immune and inflammatory responses, among which a variety of interleukins, the tumor necrosis factor alpha, the NO synthase and the cyclo-oxigenase 2 (S.
  • NF-/VB is considered an early mediator of the immune and inflammatory responses and it is involved in the control of cell proliferation and in the pathogenesis of various human diseases, among which rheumatoid arthritis (H. Beker et al., Gin. Exp.
  • HIV-1 human immunodeficiency virus
  • RNAs transcription by NF-M3 is caused by the presence of /cB-sites in the (LTR) (Long Terminal Repeats) sequences of the virus genome (M.J. Lenardo and D. Baltimore, Cell 58: 227-229, 1989).
  • LTR Long Terminal Repeats
  • HSPs Heat Shock Proteins
  • stress proteins Proc. Natl. Acad. Sci. USA 86, 8407-8411 , 1989
  • the HSPs are encoded by a cellular subgroup of genes, identified as stress genes.
  • the stress genes transcription is regulated by the trancriptional factor HSF (heat shock transcription factor) which is activated in consequence of a temperature raising, an environmental stress or after exposition to some biological molecules (R.I. Morimoto et al., J. Biol. Chem. vol. 267, 21987-21990, 1992; C. Amici et al., Proc. Natl. Acad Sci USA, vol. 89, 6227-6231 , 1992).
  • HSF heat shock transcription factor
  • Hs heat shock
  • HSP70 synthesis is one of the molecular mechanisms used by cyclopentenonic prostaglandins to cause a selective and reversible block of the protein synthesis in infection models with single strand negatively polarized RNA viruses (C. Amici et al., J. Virol. 68, 6890- 6899, 1994).
  • the cyclopentenone prostaglandin PGA inhibits the activation of NF-/ B in human cells by inhibiting the phosphorylation and degradation of the inhibitory l/ B-alpha protein (A. Rossi, G. Elia and M.G. Santoro, Proc. Natl. Acad. Sci. USA, vol.
  • the inhibitors of the activation of NF-/VB induce the activation of the HSF factor and the trancription and translation of heat shock genes, with production of hsp70.
  • Another object of the invention resides in the inhibitors of serin protease, which are strong inhibitors of the activation of NF-/VB and induce the activation of the HSF factor and the trancription and translation of heat shock genes, with production of hsp70, the HSF activation being strictly related to the inhinition of NF-/ B, both time and dose dependent.
  • a further object of the invention resides in the inhibition of the activation of NF-/VB with related induction of the activation of the HSF factor by 3,4-dichloro-iso- cuma ne (DCIC), Tosyl-L-Phenylalanine-chloromethylketone (TPCK), N ⁇ -Tosyl- Lysine-chloromethylketone (TLCK), N-acethyl-DL-Phenylalanine- ⁇ -napthylester (APNE) and N-benzoyl-L-Thyroxine-ethylester (BTEE), 3,4-dichloro-iso-cumarine (DCIC) being preferred.
  • DCIC 3,4-dichloro-iso- cuma ne
  • TPCK Tosyl-L-Phenylalanine-chloromethylketone
  • TLCK N ⁇ -Tosyl- Lysine-chloromethylketone
  • APNE N-ace
  • Another object of the invention is the use of inhibitors of NF-/VB and corresponding pharmaceutically acceptable derivative compounds as inducers of the activation of the HSF factor.
  • a further object of the invention is the use of inhibitors of NF-/ B and corresponding pharmaceutically acceptable derivative compounds as inducers of
  • HSF as medicaments with antiviral activity.
  • antiviral activity against single strand negatively polarized RNA viruses and DNA viruses e.g. herpesvirus.
  • a further object of the invention is the use of inhibitors of NF-VB and corresponding pharmaceutically acceptable derivative compounds as inducers of
  • HSF as medicaments with anti-inflammatory, anti-proliferative, immuno- suppressive, cytoprotective and antiviral activity.
  • compositions comprising inhibitors of NF-VB and corresponding pharmaceutically acceptable derivative compounds as inducers of HSF as medicaments with the above mentioned activity, in particular antiviral activity against HIV-1 virus and viruses whose replication is controlled by HSF and HSP.
  • Fig. 1A shows the activation of the HSF factor (Heat Shock Factor) by autoradiography.
  • Fig. 1B shows the activation of the HSF factor by quantitative determination.
  • Fig. 1 C shows the induction and transcription of the heat shock genes by DCIC in human leukemia by autoradiography.
  • Fig. 1 D shows the induction and transcription of the heat shock genes by DCIC in human leukemia by quantitative determination.
  • Fig. 2A shows the antiviral activity of DCIC.
  • Fig. 2B shows the induction of the HSP70 and the inhibition of the synthesis of the viral proteins by DCIC.
  • Fig. 3A shows that the HSF activation by DCIC (A) is strictly related to the inhibition of NF-ZcB.
  • Fig. 3B shows that the HSF activation by TLCK (B) is strictly related to the inhibition of NF-/ B.
  • Fig. 3C shows that the HSF activation by TPCK (C) is strictly related to the inhibition of NF-VB. detailed description of the invention
  • the inhibitors of NF-kB induce the activation of the HSF factor and the transcription and translation of heat shock genes, with production of hsp70.
  • the serin protease inhibitors can be mentioned, which are strong inhibitors of the activation of NF-/VB and which turn out to be inducers of the activation of the HSF factor and of the transcription and translation of heat shock genes, with production of hsp70, the HSF activation being strictly related to the inhibition of NF-/ B, both time and dose dependent.
  • serin protease inhibitors there are comprised: 3,4-dichloro-iso- cumarine (DCIC), Tosyl-L-Phenylalanine-chloromethylketone (TPCK), N ⁇ -Tosyl- Lysine-chloromethylketone (TLCK), N-acethyl-DL-Phenylalanine- ⁇ -napthylester (APNE) and N-benzoyl-L-Thyroxine-ethylester (BTEE). All these products are known, e.i. marketed by Sigma, Aldrich and Fluka.
  • the induction of hsp70 synthesis by the inhibitors of NF-VB is found to be associated with high antiviral activity, as previously known for other inducers of this protein.
  • VSV Vesicular Stomatitis Virus
  • the treatment with DCIC started 1 hour after infection, causes a dose-dependent reduction in the production of infectious viral particles.
  • the block in the replication of the virus is caused by the selective inibition of the synthesis of viral proteins, associated with the synthesis of hsp70 protein.
  • DCIC preferably in concentration ranging between 5 and 45 ⁇ M, is able to activate the transcription factor HSF and to selectively induce the transcription and translation of the HSP70 gene.
  • induction tests have been carried out in human leukemia cells (JURKAT cell line), as shown in Fig. 1.
  • the HSP70 synthesis is induced also in other types of human cells (HEp-2, HeLa) and in monkey epithelial cells (MA104 cells) (Fig.2). Moreover, the induction of HSP70 synthesis is found to be associated with high antiviral activity.
  • MA104 cells infected with the Vesicular Stomatitis Virus (VSV) (1-10 P.F.U./cell) the treatment with DCIC, started 1 hour after infection, causes a dose-dependent reduction in the production of infectious viral particles (Fig.2A).
  • VSV Vesicular Stomatitis Virus
  • the block in the replication of the virus is caused by the selective inibition of the synthesis of viral proteins, associated with the synthesis of HSP70 protein (Fig.2B).
  • DCIC is able to activate HSF.
  • the activation is prolonged for the following 12 hours, with a maximum at 3 hours from the beginning of the treatment.
  • hsc70 heat shock cognate 70
  • GAPDH rat glyceraldehyde phosphate dehydrogenase
  • the vector plasmid (Bluescript) was used as a non-specific hybridization control. Following hybridization, the filters were visualized by autoradiography (Fig. 1 C) and the radioactivity was quantitated by MDP analysis (Fig. 1 D).
  • VSV monkey kidney MA104 cells
  • FCS fetal calf serum
  • VSV Venezuelana serotype, Orsay; 1 P.F.U./cell
  • VSV titers were determined 12 h post infection (p.i.) by cytopathic effect 50% (CPE 50%) assay, as described in F.Pica et al., Antiviral Res., vol. 20, 193, 1993 and illustrated in Fig.
  • Uninfected (U) or VSV-infected (VSV) MA104 cells were treated with 5 ⁇ M (lanes 2 and 7), 15 ⁇ M (lanes 3 and 8), 30 ⁇ M (lanes 4 and 9) and 45 ⁇ M (lanes 5 and 10) DCIC, or with control diluent (lanes 1 and 6), soon after VSV infection and labeled with [ 35 S]-methionine (8 ⁇ Ci/2x10 5 cells, 1 h pulse starting 5 h p.i.). Equal amounts of protein were analyzed on 10% SDS/PAGE gel and processed by autoradiography. The position of hsp70, identified by western blot analysis using anti-human hsp70 antibodies, is indicated by the arrow.
  • VSV proteins L, G, N, NS and M are indicated.
  • DCIC at concentrations ranging between 5 and 45 ⁇ M, inhibits the production of VSV infectious virions from 50% to more than 98% with respect to the control, under the indicated conditions. The inhibition is mediated by a selective block of the viral protein synthesis, combined with the induction of HSP70.
  • Table 1 shows that further 4 inhibitors of serin protease, besides DCIC, activate HSF at the minimal inhibitory concentration of NF-/ B.
  • the cells were prepared according to the method described in C.Amici et al.
  • the cells were treated with DCIC, TLCK and TPCK at different concentrations for
  • Fig. 3 In Fig. 3 (lower panels) the positions of the complex NF-/VB-DNA (NF-/ B) and the non-specific bonding (ns) are indicated. In Fig. 3 (upper panels) the positions of the complex HSF-DNA (HSF), of the constitutive activity HSF-DNA (CHBA) and the non-specific interactions of proteins-DNA (ns) are indicated.
  • the line "control” refers to cells non stimulated with TPA as reference of non activated NF-M3.
  • DCIC, TLCK and TPCK activate HSF at the concentration that inhibits the NF-/VB activation by TPA.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Transplantation (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Semiconductor Integrated Circuits (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
EP98940106A 1997-07-01 1998-07-01 Inhibitors of nf-kappab as activators of hsf and inducers of heat shock proteins Withdrawn EP1003492A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITRM970392 1997-07-01
IT97RM000392A IT1293069B1 (it) 1997-07-01 1997-07-01 Inibitori di nf-kb come attivatori di hsf e induttori di proteine da shock termico
PCT/EP1998/004066 WO1999001117A2 (en) 1997-07-01 1998-07-01 Inhibitors of nf-kappab as activators of hsf and inducers of heat shock proteins

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EP1003492A2 true EP1003492A2 (en) 2000-05-31

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EP98940106A Withdrawn EP1003492A2 (en) 1997-07-01 1998-07-01 Inhibitors of nf-kappab as activators of hsf and inducers of heat shock proteins

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EP (1) EP1003492A2 (enrdf_load_stackoverflow)
JP (1) JP2002507981A (enrdf_load_stackoverflow)
AU (1) AU8854598A (enrdf_load_stackoverflow)
CA (1) CA2294764A1 (enrdf_load_stackoverflow)
IT (1) IT1293069B1 (enrdf_load_stackoverflow)
WO (1) WO1999001117A2 (enrdf_load_stackoverflow)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1289250B1 (it) 1996-12-13 1998-09-29 Consiglio Nazionale Ricerche Impiego di 2 ciclopenten 1-one e suoi derivati come inibitori del fattore nf-kb
JP2003089636A (ja) * 2001-07-12 2003-03-28 Hirofumi Kai 熱ショック蛋白質の合成抑制及び機能抑制剤
JP5697879B2 (ja) * 2010-03-12 2015-04-08 株式会社再春館製薬所 熱ショックタンパク質の発現誘導剤
JP2015042675A (ja) * 2014-11-13 2015-03-05 株式会社再春館製薬所 熱ショックタンパク質の発現誘導剤

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US4954519A (en) * 1987-04-28 1990-09-04 Georgia Tech Research Corporation Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents
DE4311835A1 (de) * 1993-04-07 1994-10-13 Boehringer Ingelheim Int Verfahren zur Inhibierung der Transkription von Genen

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See references of WO9901117A2 *

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WO1999001117A3 (en) 1999-04-01
CA2294764A1 (en) 1999-01-14
ITRM970392A0 (enrdf_load_stackoverflow) 1997-07-01
AU8854598A (en) 1999-01-25
WO1999001117A2 (en) 1999-01-14
IT1293069B1 (it) 1999-02-11
ITRM970392A1 (it) 1999-01-01
JP2002507981A (ja) 2002-03-12

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