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WO2009074809A1 - Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical - Google Patents

Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical Download PDF

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WO2009074809A1
WO2009074809A1 PCT/GB2008/004109 GB2008004109W WO2009074809A1 WO 2009074809 A1 WO2009074809 A1 WO 2009074809A1 GB 2008004109 W GB2008004109 W GB 2008004109W WO 2009074809 A1 WO2009074809 A1 WO 2009074809A1
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Prior art keywords
ikk
inhibitor
pathway
rimcazole
cells
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Barbara Spruce
Neil Perkins
Stephen Watt
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University of Dundee
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University of Dundee
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Priority to EP08859006A priority Critical patent/EP2231140A1/fr
Priority to JP2010537515A priority patent/JP2011506416A/ja
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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 materials and methods relating to the induction of cell division cycle arrest and/or apoptosis in target cells.
  • the target cells may ⁇ be tumour cells or cells involved in inflammatory disease processes .
  • WO 00/00599 teaches in particular the application of sigma ligands in tumours with constitutively active NF ⁇ B and their application in the treatment of cancer and inflammatory disease in combination with agents that activate the NF-KB pathway even in tumours that lack constitutively active NF-KB.
  • NF-KB is certainly an important regulator of programmed cell death but that it can act as either a promoter or a suppressor of cell death and/or apoptosis. This has been further extended to the notion that NF-KB can act as either a tumour promoter or suppressor (Perkins 2004 Trends in Cell Biology Vol. 14 pp64-69) .
  • WO 00/00599 claimed the broad class of NF-KB activators as providing a useful adjunct to the therapy of cancer and inflammatory disease when combined with sigma ligands .
  • WO 00/00599 taught that sigma ligands could provide a pro- apoptotic switch to NF-KB even when conferred by exogenous activators and that therefore a pro-apoptotic rather than anti-apoptotic outcome would be ensured, at least in the target (diseased) cells.
  • the invention taught against the combination of sigma ligands with inhibitors of the NF-KB pathway as this would be anticipated to antagonise the NF- ⁇ B-dependent pro-apoptotic activity of sigma ligands, including the exemplary agent rimcazole.
  • Combination regimens based on sigma ligands with NF-KB pathway inhibitors would therefore be expected to worsen the progression of cancer and inflammatory disease.
  • NF-KB pathway activation is at risk of inducing, an acute inflammatory or toxic response in normal tissues.
  • sigma ligands display strong selectivity for diseased compared to normal cells, the same does not hold for exogenous NF-KB pathway activators. Indeed, unacceptable toxicity has severely restricted the clinical application of tumour necrosis factor, a recognised NF- ⁇ B activator. Therefore, such a regimen is at risk of evoking unacceptable side-effects or toxicity.
  • Sigma ligands may still be of use in combination with sub- toxic doses of TNF etc; however, it presents risks that are inherent within the NF- KB pathway activators .
  • the invention concerns novel combinations of agents for use in the induction of apoptosis and treatment of tumour and inflammatory disease, as well as methods for identifying such agents.
  • the combinations comprise at least one sigma receptor ligand and at least one additional agent. Methods of treatment comprising said agents are also provided .
  • the additional agent (also referred to herein as a 'combination agent') is one that acts as a selective inhibitor of the anti-apoptotic I- ⁇ B kinase (IKK)/NF- ⁇ B pathway but does not inhibit a pro-apoptotic arm of IKK/NF- ⁇ B pathway function.
  • IKK anti-apoptotic I- ⁇ B kinase
  • Exemplary combination agents include proteasome inhibitors such as MG132 and bortezomib (also known as Velcade or PS341) ; thalidomide and thalidomide analogues; and histone deacetylase (HDAC) inhibitors such as sodium valproate.
  • Said agents also include inhibitors of the kinase mTOR that also lies downstream from anti-apoptotic IKK; mTOR inhibitors would include rapamycin and its analogues ⁇ "rapalogs” ) .
  • Said agents also include tyrosine kinase inhibitors that inhibit the Pl-3 kinase pathway and thence Akt (PKB) and its downstream target IKK. They may be identified by the assays described herein.
  • a method of treatment of tumour comprising administering to a patient in need thereof
  • a sigma receptor ligand (i) a sigma receptor ligand, and (ii) an IKK/NF- ⁇ B inhibitor which inhibits an anti-apoptotic arm of the IKK/NF- ⁇ B pathway and does not inhibit a pro- apoptotic arm of the IKK/NF- ⁇ B pathway, either sequentially or in combination.
  • said agents are provided in a pharmaceutically effective amount, or said combination is provided in a pharmaceutically effective amount.
  • the invention provides a method of treatment of inflammatory disease comprising administering to a patient in need thereof
  • an IKK/NF- ⁇ B pathway inhibitor which inhibits an anti- apoptotic arm of the IKK/NF- ⁇ B pathway and does not inhibit a pro-apoptotic arm of the IKK/NF- ⁇ B pathway, either sequentially or in combination.
  • said agents are provided in a pharmaceutically effective amount, or said combination is provided in a pharmaceutically effective amount.
  • a sigma receptor ligand in combination with an IKK/NF- ⁇ B pathway inhibitor which inhibits an anti-apoptotic arm of the IKK/NF- ⁇ B pathway and does not inhibit a pro-apoptotic arm of the IKK/NF- ⁇ B pathway, in the manufacture of a medicament for the treatment of tumour of inflammatory disease.
  • a sigma receptor ligand in combination with an IKK/NF-KB pathway inhibitor which inhibits an anti- apoptotic arm of the IKK/NF- ⁇ B pathway and does not inhibit a pro-apoptotic arm of the IKK/NF- ⁇ B pathway, for use in the treatment of tumour of inflammatory disease
  • a composition comprising a sigma receptor ligand and an IKK/NF-KB pathway inhibitor which inhibits an anti-apoptotic arm of the IKK/NF- ⁇ B pathway and does not inhibit a pro-apoptotic arm of the IKK/NF- ⁇ B pathway, for the treatment of tumour or inflammatory disease.
  • composition comprising a sigma receptor ligand and a IKK inhibitor which inhibits an anti-apoptotic arm of the IKK pathway and does not inhibit a pro-apoptotic arm of the IKK/NF-KB pathway.
  • kits for treatment of cancer or inflammatory disease comprising a sigma receptor ligand and a IKK inhibitor which inhibits an anti-apoptotic arm of the IKK pathway and does not inhibit a pro-apoptotic arm of the IKK/NF- ⁇ B pathway.
  • the kit may optinally include instructions for use in treatment of cancer or inflammatory disease.
  • a preferred sigma ligand is rimcazole, including rimcazole variants and analogues such as those shown in annex 1.
  • Particularly preferred combination agents include proteasome inhibitors such as MG132 and bortezomib (also known as Velcade or PS341); thalidomide and thalidomide analogues; and histone deacetylase (HDAC) inhibitors such as sodium valproate.
  • proteasome inhibitors such as MG132 and bortezomib (also known as Velcade or PS341); thalidomide and thalidomide analogues; and histone deacetylase (HDAC) inhibitors such as sodium valproate.
  • Said agents also include inhibitors of the kinase mTOR that also lies downstream from anti-apoptotic IKK; mTOR inhibitors would include rapamycin and its analogues ( "rapalogs”) .
  • Said agents also include tyrosine kinase inhibitors that inhibit the PI-3 kinase pathway and thence Akt (PKB) and its downstream target IKK.
  • Suitable tyrosine kinase inhibitors include inhibitors of the EGF receptor, as described below.
  • Suitable combination agents may be identified by the assays described herein.
  • the tumour may be cancer, for example myelocytic leukaemia, multiple myeloma, non small cell lung cancer, breast cancer, glioblastoma, melanoma, colorectal cancer, ovarian cancer.
  • the method comprises i) contacting a test population of cells with a sigma receptor ligand, and assaying for cell death; ii) contacting a test population of cells with a sigma receptor ligand in combination with a test agent, and assaying for cell death; iii) contacting a test population of cells with a sigma receptor ligand in combination with said test agent and an IKK inhibitor and assaying for cell death; wherein a positive result is obtained when the amount of cell death occurring at (ii) exceeds that at (i) and at (iii) .
  • the test agent may be an agent known to be an inhibitor of at least a part of the IKK/NF-KB pathway.
  • the IKK inhibitor is an inhibitor of the pro-apoptotic component of IKK/NF- ⁇ B pathway function, identifiable by its capacity to attenuate sigma ligand induced death when provided in combination with a sigma ligand.
  • the present invention in contrast, teaches that the subset of IKK inhibitor compounds that are of use as agents in the assay of the invention - to identify suitable combination agents - are in turn identifiable by their capacity to attenuate rimcazole- induced death, rimcazole being an exemplary inducer of IKK in pro-apoptotic mode.
  • the sigma receptor ligand is rimcazole
  • the test population of cells is HL-60
  • the IKK inhibitor is BAY 11-7082, parthenolide, IMD 0354 and SC514.
  • Rimcazole-mediated cell death is substantially attenuated by certain small molecule inhibitors of the NF- ⁇ B pathway, such as inhibitors of the I- ⁇ B kinase (IKK) complex and in particular by IKK2 inhibitors.
  • IKK I- ⁇ B kinase
  • IKK inhibitors In contrast to their usual death-enhancing effect, many IKK inhibitors have an opposite effect in combination with sigma ligands which is to attenuate cell death. Taken together with the ability of rimcazole to activate the IKK/NF-KB pathway in pro-apoptotic mode, the conclusion is that many IKK inhibitors are inhibiting pro- as well as anti-apoptotic arms of the IKK/NF-KB pathway and as such are antagonising rather than enhancing the cell killing effects of rimcazole and other sigma ligands.
  • rimcazole-induced death by certain IKK inhibitors is presumptively due to inhibition of the pro- apoptotic as well as the anti-apoptotic arm of the IKK/NF-KB pathway.
  • the inventors have suprisingly discovered that combining rimcazole, or other sigma ligands, with more selective inhibitors of the anti-apoptotic arm of the IKK/NF-KB pathway can leave the pro-apoptotic arm uninhibited and lead to enhanced cell death particularly in cells that are primed with constitutively active IKK/NF-KB, such as tumour and inflammatory cells.
  • an agent to evoke anti-inflammatory and/or anti-tumour activity does not of itself predict that it will be useful in combination with rimcazole or other sigma ligands to enhance activity in cancer or inflammatory disease. Indeed, some agents that are useful as anti-tumour agents on their own will inhibit the anti-tumour or inflammatory activity of rimcazole and other sigma ligands. This is taught very clearly herein.
  • the IKK/NF-KB inhibitor BAY 11-7082 and derivatives of it, are known in the art as potential agents to treat tumours and leukaemias.
  • BAY 11-7082 induces apoptosis in myeloma cells and synergises with the checkpoint abrogator UCN-01 to enhance apoptosis, implying that the two agents will be useful in combination therapy (Dai et al . , 2004 Blood Vol. 103 pp2761-2770) .
  • the present invention in contrast shows very clearly that BAY 11-7082 antagonises apoptosis induction by rimcazole and will therefore not be of use to enhance the clinical action of rimcazole and other sigma ligands .
  • the IKK/ NF-KB pathway inhibitor As another illustration, the IKK/ NF-KB pathway inhibitor, parthenolide, displays anti-tumour and anti -angiogenic activity in vitro and in vivo and has been progressed to Phase 1 dose-escalating trials in humans with cancer (Curry et al 2004 Invest New Drugs Vol. 22 pp299-305) .
  • a parthenolide analogue with improved pharmacokinetic properties is being progressed towards clinical trials in cancer.
  • Agents that are of use as combination agents to enhance the therapeutic activity of rimcazole and other sigma ligands can be identified from this invention as those that fall within the broad class of IKK/NF-KB pathway inhibitor but that are restricted to the subset that act as selective inhibitors of an anti-apoptotic arm of the IKK/NF-KB pathway and that in turn fall within the following groups of agents: proteasome inhibitors, a subset of HDAC inhibitors, thalidomide and its analogues, tyrosine kinase inhibitors, mTOR inhibitors and hsp90 inhibitors including geldanamycin and its analogues such as 17-AAG.
  • IKK inhibitors that inhibit a pro-apoptotic arm of the IKK/NF- KB pathway are not of use in combination with rimcazole and sigma ligands to treat disease but are of as agents to identify potential combination agents, for example in the assays described above.
  • the inventors have therefore shown a clear distinction between the action of IKK/NF-KB pathway inhibitors that inhibit a pro- apoptotic component of IKK/ NF-KB function and other agents such as proteasome inhibitors that selectively inhibit the anti-apoptotic arm of NF-KB function.
  • IKK/NF-KB pathway inhibitors that inhibit a pro- apoptotic component of IKK/ NF-KB function
  • other agents such as proteasome inhibitors that selectively inhibit the anti-apoptotic arm of NF-KB function.
  • proteasome inhibitors that selectively inhibit the anti-apoptotic arm of NF-KB function.
  • Synergistic death induction is exemplified in a range of solid tumour types including estrogen receptor (ER) negative breast cancer, lung cancer and glioblastoma; also, in haematological malignancies including acute myeloid leukaemia and multiple myeloma.
  • ER estrogen receptor
  • haematological malignancies including acute myeloid leukaemia and multiple myeloma.
  • proteasome inhibitors resemble IKK inhibitors in enhancing tumour cell death which is consistent with an inhibitory effect on the anti-apoptotic function of NF-KB but does not teach a distinction between broad inhibition of both pro-and anti-apoptotic arms of IKK/NF-KB functions versus selective inhibition of an anti-apoptotic function. To do so would require use of a system in which the pro-apoptotic function of NF-KB is revealed.
  • the present invention now teaches that a certain specific category of IKK/NF-KB pathway inhibitor is of use to enhance rimcazole and sigma ligand-induced death but this is confined to agents that selectively inhibit the anti-apoptotic arm of IKK/NF-KB function and that therefore leave the pro-apoptotic arm of IKK/NF-KB function uninhibited.
  • IKK/NF-KB pathway inhibitor is of use to enhance rimcazole and sigma ligand-induced death but this is confined to agents that selectively inhibit the anti-apoptotic arm of IKK/NF-KB function and that therefore leave the pro-apoptotic arm of IKK/NF-KB function uninhibited.
  • One such type of agent is exemplified by MG132.
  • a report from Dai et al . (2003 Oncogene Vol. 22 pp7108-7122) further describes a reduction in the DNA binding of NF-KB in response to MG132 and synergy between MG132 and cdk inhibitors such as flavopiridol in enhancing leukaemic cell death.
  • the IKK inhibitor BAY 11-7082 is reported to enhance flavopiridol -induced apoptosis which contrasts with the teaching in the present invention that rimcazole-induced death is attenuated by the same IKK inhibitor; thus, flavopiridol and other cdk inhibitors do not require NF-KB for apoptosis induction and therefore are distinct from rimcazole and other sigma ligands.
  • the report from Dai et al . therefore teaches that MG132 and IKK inhibitors act in an equivalent way to enhance apoptosis induction when combined with cdk inhibitors .
  • the present invention in contrast teaches that proteasome inhibitors such as MG132, despite an inhibitory effect upon NF- ⁇ B, enhance the killing of leukaemic and solid tumour cells in response to rimcazole. This is in stark contrast to the effect of IKK/NF- ⁇ B pathway inhibitors that inhibit a pro-apoptotic arm of the IKK/NF-KB pathway, which is to attenuate rather than enhance rimcazole-induced cell killing.
  • the inventors further show that the synergy between rimcazole and MG132 is dependent upon IKK/NF-KB pathway activation. This is revealed by marked attenuation of death when an IKK/NF-KB pathway inhibitor is provided in triple combination with an exemplary sigma ligand such as rimcazole and an exemplary proteasome inhibitor such as MG132. This is consistent with inhibition of a pro-apoptotic arm of IKK/NF-KB function by certain IKK/NF-KB pathway inhibitors, in contrast to a selective inhibition of the anti-apoptotic function of NF-KB by the exemplary proteasome inhibitor MG132.
  • a further class of combination agent is a subset of the so-called histone deacetylase inhibitor (HDACi) class of agent that is already known in the art as an anti-cancer agent both as a monotherapy and in combination with other agents .
  • HDACi ' s have a complex relationship with the NF-KB pathway, however, being variously reported as NF-KB pathway inhibitors or activators.
  • the HDAC inhibitor sodium valproate (or valproic acid) a known anti-epileptic and anti-cancer drug, has been reported to inhibit NF-KB activity (Ichiyama 2000 Brain Research Vol. 857 pp246 ⁇ 251; Ogbomo et al . 2007 FEBS Lett. Vol.
  • HDACi ' s activate the NF-KB pathway in an anti-apoptotic mode (Kim et al . , 2006 Cell Death and Differentiation Vol. 13 pp2033-2041; Dai et al . , 2005 Molecular and Cellular Biology Vol. 25 pp5429-5444) .
  • the present inventors have surprisingly identified a subset of HDAC inhibitors -exemplified herein by sodium valproate - which are selective inhibitors of an anti-apoptotic arm of IKK/NF-KB pathway function that leave a pro-apoptotic arm uninhibited.
  • sodium valproate also known as valproic acid
  • a particular embodiment of the invention therefore is to use sodium valproate (also known as valproic acid) , and its derivatives, in combination with rimcazole or other sigma ligands in order to treat cancer and inflammatory disease.
  • a alternative combination agent is thalidomide and analogues of thalidomide. These agents are known in the art as NF- ⁇ B pathway inhibitors (Kobayashi et al . , Cancer Research 65: 10464-10471, 2005 ⁇ but thus far, not as selective inhibitors of an anti-apoptotic arm of IKK/NF-KB pathway function. The present inventors have demonstrated that such agents act as selective inhibitors of an anti-apoptotic arm of IKK/NF- ⁇ B pathway function.
  • mTOR mediates an anti-apoptotic function and is known to be activated by IKK (Dan et al . , Cancer Res. 67:6263- 6269, 2007) . It is disclosed herein that inhibitors of mTOR act to selectively inhibit an anti-apoptotic arm of the IKK pathway and will therefore cooperate with rimcazole and other sigma ligands, agents that engage IKK/ NF- ⁇ B in a pro- apoptotic mode, in anti-tumour and anti-inflammatory effects. Inhibitors of mTOR are suitably captured by the assays described herein to identify suitable combination agents that relies upon their participation in the IKK pathway.
  • a further class combination agents is tyrosine kinase inhibitors that inhibit the PI-3 kinase pathway and thence Akt (PKB) .
  • IKK is known to be activated by Akt (Agarwal et al . ,
  • Tyrosine kinase inhibitors are known in the art as IKK/NF-KB pathway inhibitors (An et al . MoI. Cancer Ther. 6(1) : 61-69, 2007; Appel et al . , Clin. Cancer Res. 11(5) : 1928-1940, 2005) but not as selective inhibitors of an anti-apoptotic arm of IKK/NF-KB pathway function that leaves a pro-apoptotic arm of IKK pathway unhindered.
  • Tyrosine kinase inhibitors that are of particular use in combination with rimcazole and other sigma ligands in the treatment of cancer are those that fall within the class of epidermal growth factor receptor (EGFR) inhibitors.
  • EGFR epidermal growth factor receptor
  • Activation of the EGFR is known to drive activation of the NF- ⁇ B pathway in a range of tumours including prostate (Le Page et al . , 2005 The Prostate 65(2) : 130-140), ER negative breast cancer (Van Laere et al., 2007 Br J Cancer 97(5) 659-669) and non small cell lung cancer (Sethi et al., 2007 Oncogene 26(52) : 7324- 7332.)
  • EGFR inhibition selectively inhibits an anti-apoptotic arm of NF- ⁇ B function, without inhibiting its pro-apoptotic activity, to cause an enhancement of rimcazole-mediated cell death in tumour cells.
  • a small molecule inhibitor of the EGFR gefitinib (also known as Iressa) . Iressa is therefore of particular use as a combination agent .
  • Another class of combination agent is the class of hsp-90 inhibitors that includes geldanamycin and the geldanamycin analogue 17- (allylamino) -17-demethoxygeldanamycin (17-AAG, NSC 330507) and other geldanamycin derivatives.
  • 17-AAG is known in the art as an inhibitor of TNF-mediated NF-kappaB activation in lung cancer cells (Wang et al 2006 Cancer Research Vol. 66 ppl089-1095) but not as a selective inhibitor of NF- ⁇ B-mediated anti-apoptotic function.
  • this class of agent is of use to selectively inhibit an anti-apoptotic arm of the NF-KB pathway that will therefore enhance sigma ligand-induced cell killing, mediated by pro-apoptotic induction of the IKK/NF- ⁇ B pathway.
  • Figure 1 shows I- ⁇ B levels by immunoblot in HL-60 (acute promyelocytic leukaemia) and 0PM2 (multiple myeloma) cells after treatment with rimcazole for 2 (HL-60), 4 (OPM-2) and 24 hours. Actin immunoblot confirmed uniform loading.
  • Figure 2 is an EMSA (electrophoretic mobility shift assay) in H1299 lung cancer cells showing binding of NF- ⁇ B to the HIV KB consensus site induced by rimcazole. TNF was used as a positive control .
  • Figure 3 shows the effect of rimcazole on cell number, expressed relative to drug vehicle-treated control cells, in H1299 (lung cancer) cells treated with siRNA to ReIA (p65) (dark bars) compared with control, non-targeting siRNA (hatched bars) . Values are expressed as mean ( ⁇ SEM) . Cells in which ReIA (p65) had been knocked down at the time of exposure to 20 micromolar rimcazole were substantially protected from its cell killing and growth inhibitory effects.
  • Figure 4 shows the effect of rimcazole, with and without the NF- ⁇ B inhibitor JSH-23, on cell number in H1299 cells.
  • Diamonds control.
  • Filled triangles 12.5 micromolar rimcazole.
  • Crosses 10 micromolar JSH-23.
  • Open triangles, dashed line 12.5 micromolar rimcazole and 10 micromolar JSH- 23.
  • Figure 5 shows the effect of rimcazole on cell number in HL- 60 cells expressing a super-repressor form of 1- ⁇ B (dashed lines) or vector only control (solid lines) .
  • Rimcazole was added at 3.125 micromolar (diamonds) , 6.25 micromolar (triangles) and 12.5 micromolar (squares) .
  • Figure 6 shows the effect of rimcazole and BAY 11-70782 on cell number in HL-60 cells.
  • Diamonds control. Filled squares: 12.5 micromolar rimcazole. Triangles: 5 micromolar BAY 11-7082. Circles: 0.5 micromolar BAY 11-7082. Open squares: 0.5 micromolar BAY 11-7082 and 12.5 micromolar rimcazole.
  • Figure 7 shows the effect of rimcazole on cell number in HL-60 cells with and without the IKK inhibitor parthenolide.
  • Figure 8 shows the effect of rimcazole on cell number in HL-60 cells with and without the IKK inhibitor IMD 0354.
  • Figure 9 shows the effect of rimcazole on cell number in H1299 cells with and without the IKK inhibitor SC-514.
  • Figure 10 shows the effect of rimcazole on cell number in HL- 60 cells with and without the proteasome inhibitor MG132.
  • Figure 12 shows the effect of rimcazole on cell number in MDA- MB231 cells with and without the proteasome inhibitor MG132.
  • Diamonds control.
  • Squares 0.1 micromolar MG132.
  • Filled triangles 12.5 micromolar rimcazole.
  • Open triangles, dashed line 12.5 micromolar rimcazole and 0.1 micromolar MG132.
  • Figure 13 shows the effect of rimcazole on cell number in U118 cells with and without the proteasome inhibitor MG132.
  • Diamonds control.
  • Squares 0.1 micromolar MG132.
  • Filled triangles 12.5 micromolar rimcazole.
  • Figure 14 shows the effect of rimcazole on cell number in H1299 cells with and without the proteasome inhibitor bortezomib (Velcade) .
  • Diamonds control.
  • Filled triangles 20 micromolar rimcazole.
  • Crosses 7 nanomolar Velcade.
  • Open triangles, dashed line 20 micromolar rimcazole and 7 nanomolar Velcade
  • Figure 15 shows the effect of rimcazole on cell number in HL- 60 cells with and without the proteasome inhibitor MG132 and the IKK inhibitor BAY 11-7082.
  • Figure 16 shows the effect of rimcazole on cell number in HL- 60 cells with and without the proteasome inhibitor MG132 and the IKK inhibitor BAY 11-7082.
  • Figure 17 shows the effect of rimcazole on cell number in HL- 60 cells with and without the proteasome inhibitor MG132 and the IKK inhibitor parthenolide.
  • Diamonds control. Filled squares: 6.25 micromolar rimcazole. Triangles: 0.1 micromolar MG132. Open squares 6.25 micromolar rimcazole and 0.1 micromolar MG132. Crosses: 6.25 micromolar rimcazole, 0.1 micromolar MG132 and 5 micromolar parthenolide.
  • Figure 18 shows the effect of rimcazole on cell number in HL- 60 cells with and without the HDAC inhibitor sodium valproate.
  • Diamonds control.
  • Filled triangles 6.25 micromolar rimcazole.
  • Crosses 1 millimolar sodium valproate.
  • Squares 0.5 millimolar sodium valproate.
  • Figure 19 shows the effect of rimcazole on cell number in H1299 cells with and without the HDAC inhibitor sodium valproate.
  • Figure 20 shows the effect of rimcazole on cell number in MDA MB 231 cells with and without the HDAC inhibitor sodium valproate. Diamonds: control. Filled squares: 12.5 itiicromolar rimcazole. Filled triangles: 1 millimolar sodium valproate. Open squares: 12.5 micromolar rimcazole and 1 millimolar sodium valproate.
  • Figure 21 shows the effect of rimcazole on cell number in UIl 8MG cells with and without the HDAC inhibitor sodium valproate.
  • Figure 22 shows the effect of rimcazole on viable cell number in H1299 NSCLC cells with and without the EGFR inhibitor gefitinib.
  • Figure 23 shows the effect of rimcazole on viable cell number in MDA-MB-468 breast cancer cells with and without the EGFR inhibitor gefitinib.
  • Sigma Receptor Ligands Specific sigma receptor ligands bind to sigma receptors in substantial preference to other known receptors such as classical opioid receptors - mu, delta, kappa, - dopamine, serotonin, phencyclidine, and beta - adrenergic receptors.
  • a ligand for a sigma receptor can be identified in accordance with the method disclosed in Vilner et al, Cancer Res. ,55(2) :408-413, 1995.
  • the binding of a putative sigma ligand to sites on sigma receptors can be measured by comparison to the prototypic sigma ligands such as (+ ⁇ -pentazocine (to assay sigma-1 site binding) and 1, 3-di-o-tolylguanidine (DTG) (to assay sigma-2 site binding), and as described by Walker et al . , Pharmacological Reviews, 42:355-400, 1990.
  • Radio or chemically labelled prototype sigma ligands are allowed to bind to sigma receptors in the cell preparation. The amount of labelled prototype sigma ligand displaced by the putative ligand is measured and used to calculate the affinity of the putative ligand for the sigma receptor.
  • Sigma receptor refers to the different forms of sigma receptors (sigma 1, sigma 2 receptors, etc) and to isoforms such as splice variants thereof.
  • Sigma receptor- binding assays are disclosed for example in Vilner et al . , Cancer Research 55(2) : 408-413, 1995 and typically involve making a suitable preparation such as a crude membrane portion, using conventional protocols, from a cell type, such as a human tumour cell line, which is known to express sigma receptors.
  • Examples of such cell lines would include; A375 melanoma (Accession No: ECACC 88113005) , SK-N-SH neuroblastoma (Accession No: ECACC 86012802) and LNCaP. FGC prostate (Accession No.- ECACC 89110211) . These cell lines are obtainable from the European Collection of Animal Cell Cultures (Porton Down, England) with reference to the accession numbers shown.
  • sigma binding sites located within the same receptor or on different sigma receptor types have the potential to be either anti- or pro- death and therefore the capacity of sigma ligands to occupy sigma sites is insufficient to predict therapeutic efficacy.
  • WO 00/00599 elucidated a method that combines sigma site binding (typically by radioligand binding assay) and a functional "in vitro" assay for cell-selective death and/or proliferation inhibition that can be conducted by anyone skilled in the art . This is particularly required given that some sigma ligands are preferentially targeted to normal rather than tumour tissue.
  • an assay to identify an agent as a sigma ligand (but not whether it is an agonist -. stimulator - or antagonist - inhibitor) with an assay to determine cell-selective death is required to define the agents of the invention.
  • Sigma ligands of use in the treatment of tumour and inflammatory disease comprise agents that display three essential features: i) binding to sigma receptors in substantial preference to other known receptors, where sigma receptors include sigma-1 and sigma-2 receptors and isoforms of sigma receptors such as splice variants; ii) induction of cell death and/or inhibition of proliferation in cells that are wholly or partly reliant on autocrine signals (factors from cells of the same type) for survival.
  • self-reliant cells include diseased cells, such as tumour and persistent inflammatory cells, and non-diseased, "normal” cells that display atypical properties of survival regulation such as microvascular endothelial cells and lens epithelial cells; iii) lack of toxicity towards normal cells that possess typical properties of survival and proliferation regulation such as a requirement for signals from other cell types in order to survive in vivo; such cells include normal, finite life span (non-immortal) proliferating or non-proliferating, epithelial cells, fibroblasts or lymphoid cells.
  • WO 00/00599, WO 01/074359A1 and WO 06/021811A2 are diseases that are associated with fibroblasts.
  • Preferred sigma ligands include sigma-1 antagonists, sigma-2 agonists and mixed sigma-1 antagonist/sigma-2 agonist compounds where i) sigma-1 antagonists are defined as agents that bind to the sigma-1 receptor and repress the survival function of the sigma-1 receptor in such a way as to cause a net reduction in self-reliant (tumour, inflammatory or other target population) cell number in comparison to untreated self-reliant cells and sigma-1 antagonist-treated non-self- reliant cells; ii) sigma-2 agonist compounds are defined as agents that bind to the sigma-2 receptor and stimulate the pro-death function of the sigma-2 receptor in such a way as to cause a net reduction in self-reliant (tumour, inflammatory or other target population) cell number in comparison to untreated self-reliant cells and sigma-2 agonist-treated non- self-reliant cells.
  • sigma receptor ligands that are of use in the invention include : rimcazole (cis-9- [3 , 5 -dimethyl- 1- piperazinyl ) propyl ] carbazole) ; rimcazole variants, in particular pharmaceutically acceptable salts such as rimcazole dihydrochloride (cis-9- [3 , 5-dimethyl- 1-piperazinyl) propyl] carbazole dihydrochloride) ; rimcazole variants including 3 , 6-Dibromo-9- [3- [cis-3 , 5- dimethyl-1-piperazinyl) -propyl] carbazole Hydrochloride (5) and 1,3, 6-Tribromo-9- [3- ( ⁇ is ⁇ 3 , 5-dimethyl-1- piperazinyl) propyl] carbazole Hydrochloride, 3-Nitro-9- [3- [cis- 3 , 5-dimethyl-l-piperazinyl) propyl] carb
  • JJC2-006 JJC2-008 (see structures at Appendix) and related compounds as disclosed in Husbands et al . , J. Med Chem. 42:
  • IPAG (1- (4-iodophenyl) -3- (2-adamantyl) guanidine. haloperidol , reduced haloperidol and other drugs within the butyrophenone class
  • SH344 Siramesine and siramesine variants and analogues SR 31747 and SSR 125329
  • panamesine fluvoxamine, sertraline,
  • a preferred sigma receptor ligand is Rimcazole (BW 234U) (cis- 9- [3 , 5-dimethyl-l-piperazinyl) propyl] carbazole dihydrochloride) , a compound known to have activity as an anti-psychotic, e.g. see US Patent No: 5,955,459, and as an agent which blocks the activity of cocaine (Menkel et al, Eur. J. Pharmacol., 201:251-252, 1991).
  • a range of Rimcazole variants are known (see above, Husbands et al 1999 and Cao et al 2003) .
  • ligands include rimcazole variants, in particular pharmaceutically acceptable salts such as rimcazole dihydrochloride; rimcazole solvates such as hydrates or alcoholates; rimcazole analogues, where the core structure of rimcazole has been changed to create a structurally related but distinct chemical compound; rimcazole metabolites; IPAG; haloperidol and reduced haloperidol; ibogaine.
  • pharmaceutically acceptable salts such as rimcazole dihydrochloride
  • rimcazole solvates such as hydrates or alcoholates
  • rimcazole analogues where the core structure of rimcazole has been changed to create a structurally related but distinct chemical compound
  • rimcazole metabolites IPAG
  • haloperidol and reduced haloperidol ibogaine.
  • Rimcazole can be readily produced by those skilled in the art, e.g. using the following synthesis for Rimcazole dihydrochloride (9-3- ((3R, 5S)-3,5 dimethyl-piperazin-1-yl) - propyl- 9H-carbazole dihydrobromide) .
  • a synthetic route to produce synthon A can be adapted from Whitmore et al, JACS, 66:725-731, 1944.
  • the synthesis of B can be carried out using the stereospecific synthesis of trans compounds shown in Harfenist et al, JOC, 50:1356-1359, 1985.
  • the two precursors can then be coupled to produce Rimcazole dihydrochloride .
  • the present invention also includes methods of identifying a combination agent of the invention.
  • the invention provides methods of identifying agents which inhibit an anti-apoptotic arm of the IKK/NF ⁇ B pathway but do not inhibit a pro-apoptotic arm of the IKK/NF ⁇ B pathway activated by sigma ligands .
  • a sigma receptor ligand such as rimcazole
  • attenuation of death when the two agents are further combined with one or more agents that belong to the class of IKK/NF- ⁇ B pathway inhibitor that inhibits a pro-apoptotic component of IKK/NF- ⁇ B pathway function.
  • An exemplary method comprises : i) contacting a test population of cells with a sigma receptor ligand, and assaying for cell death; ii) contacting a test population of cells with a sigma receptor ligand in combination with a test agent, and assaying for cell death,- iii) contacting a test population of cells with a sigma receptor ligand in combination with said test agent and an IKK inhibitor; preferably a non-selective IKK inhibitor or a selective IKK2 inhibitor, and assaying for cell death; wherein the amount of cell death occurring at (i) is less than that at (ii) and more than that at (iii) .
  • IKK inhibitors include BAY 11-7082, ((E)3-[(4- Methylphenyl ) sulfonyl] -2-propenenitrile) , parthenolide
  • IMD 0354 N- (3 , 5-Bis-trifluoromethylphenyl) -5- chloro-2-hydroxybenzamide)
  • BAY 11-7085 (E)3-[ (4-t- Butylphen ⁇ l)sulfonyl]-2-propenenitrile) , wedelolactone (7- Methoxy-5,ll,12-trihydroxy-coumestan)
  • BMS-345541 (4- (2'- Aminoethyl)amino-l,8-dimethylimidazo[l,2-a]quinoxaline)
  • IKK2 inhibitor IV [5- (p-Fluorophenyl) -2-ureido] thiophene-3- carboxamide
  • IKK2 inhibitor VI (5-Phenyl-2-ureido) thiophene- 3-carboxamide)
  • SC-514 PS1145, IKK inhibitor peptide (cell permeable) (Ac-
  • a preferred cell system in which to conduct the assay is a myelocytic leukaemia cell line such as the HL-60, AML193, CTV- 1, EOL-I, GF-D8, KASUMI-I 7 KG-I, KG-Ia, ML3 , MVTZ-2, MV4-11, OCI-AML2, OCI-AML5, PLB-985, UT-7 cell lines.
  • myelocytic leukaemia cell line such as the HL-60, AML193, CTV- 1, EOL-I, GF-D8, KASUMI-I 7 KG-I, KG-Ia, ML3 , MVTZ-2, MV4-11, OCI-AML2, OCI-AML5, PLB-985, UT-7 cell lines.
  • the test agent is a proteasome inhibitor or a HDAC inhibitor.
  • proteasome inhibitors that can be used as combination agents in therapy or as test agents in the assay include MG132, bortezomib (Velcade, PS341, [ (IR) -3 -methyl-1- [ [ (2S)-l-oxo-3-phenyl-2-
  • HDAC inhibitors that can be used as combination agents in therapy or as test agents include sodium valproate (valproic acid) , benzoylaminoalkanohydroxamic acids including 5- (4-dimethylaminobenzoyl) aminovaleric acid hydroxamide (4 ⁇ Me 2 N-BAVH), FR901228 (FK228) , FR235222.
  • sodium valproate valproic acid
  • benzoylaminoalkanohydroxamic acids including 5- (4-dimethylaminobenzoyl) aminovaleric acid hydroxamide (4 ⁇ Me 2 N-BAVH)
  • FR901228 FK228)
  • FR235222 FR235222.
  • the combination agent or test agent is an analogue of thalidomide or a tyrosine kinase inhibitor, which are also known in the art as NF- ⁇ B pathway inhibitors (Kobayashi et al . , Cancer Research 65: 10464-10471, 2005;
  • Exemplary thalidomide analogues include thalidomide itself (2- (2, 6-dioxo-3-piperidyl) isoindole-1, 3-dione) , lenalidomide (Revlimid, CC-5013) , ACTIMID (CC-4047) , CC-1069, CC-3052, CPSIl, CPS49, thiothalidoitiides , N- substituted and tetrafluorinated thalidomide analogues .
  • tyrosine kinase inhibitors include trastuzumab
  • Gefitinib Iressa
  • Erlotinib Tarceva
  • Lapatinib Tykerb
  • Cetuximab Erbitux
  • HKI-272 HKI-357
  • EKB-569 EKB-569
  • CL- 387,785 TheraCIM
  • Panitumumab ABX-EGF
  • Matuzumab Nimotuzumab
  • Zalutumumab are EGFR receptor inhibitors.
  • the combination agent or test agent is an inhibitor of mTOR that is activated in its anti- apoptotic mode by IKK; therefore, inhibitors of mTOR such as rapamycin and its analogues ( "rapalogs" ) act as selective inhibitors of the anti-apoptotic arm of an IKK pathway and as such are captured by the method described herein to identify suitable combination agents .
  • Exemplary mTOR inhibitors include rapamycin and its analogues such as temsirolimus (CCI-779, Torisel) , everolimus (RADOOl) , AP23573 and agents recited in patents US 5,527,907, US 6,984,635 and US 6,187,757.
  • test substance or compound which may be added to an assay of the invention will normally be determined by trial and error depending upon the type of compound used.
  • proliferation/survival assays will typically employ 0.1 to 100 ⁇ M of the test compound.
  • Compounds which may be used may be natural or synthetic chemical compounds used in drug screening programmes . Extracts of plants which contain several characterised or uncharacterised components may also be used. Other candidate compounds may be based on modelling the 3 -dimensional structure of a polypeptide or peptide fragment and using rational drug design to provide potential inhibitor compounds with particular molecular shape, size and charge characteristics .
  • the substance or agent may be investigated further. Furthermore, it may be manufactured and/ or used in preparation, i.e. manufacture or formulation, of a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals.
  • the agents of the invention may be derivatised in various ways.
  • derivatives of the compounds includes salts, esters and amides, free acids or bases, hydrates, prodrugs or coupling partners .
  • Salts of the compounds of the invention are preferably physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art .
  • Compounds having acidic groups such as phosphates or sulfates, can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tr ⁇ s (2-hydroxyethyl)amine.
  • Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • Compounds having both acidic and basic groups can form internal salts.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art .
  • Derivatives which act as prodrugs of the compounds are convertible in vivo or in vitro into one of the compounds.
  • at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • prodrug therapy is the use of an antibody specific for a disease marker on a cell coupled to an enzyme capable of converting a prodrug to active drug or toxin.
  • Coupled derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it.
  • coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug or an inhibitor.
  • Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • compositions The agents described herein or their derivatives can be formulated in pharmaceutical compositions, and administered to patients in a variety of forms .
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may include a solid carrier such as gelatin or an adjuvant or an inert diluent.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • Such compositions and preparations generally contain at least 0. lwt% of the compound.
  • Parental administration includes administration by the following routes : intravenous , cutaneous or subcutaneous , nasal, intramuscular, intraocular, transepithelial, intraperitoneal and topical (including dermal, ocular, rectal, nasal, inhalation and aerosol), and rectal systemic routes.
  • routes for intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen- free and has suitable pH, isotonicity and stability.
  • suitable solutions using, for example, solutions of the compounds or a derivative thereof, e.g. in physiological saline, a dispersion prepared with glycerol, liquid polyethylene glycol or oils.
  • compositions can comprise one or more of a pharmaceutically acceptable excipient, carrier, buffer, stabiliser, isotonicizing agent, preservative or anti-oxidant or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material may depend on the route of administration, e.g. orally or parentally.
  • Liquid pharmaceutical compositions are typically formulated to have a pH between about 3.0 and 9.0, more preferably between about 4.5 and 8.5 and still more preferably between about 5.0 and 8.0.
  • the pH of a composition can be maintained by the use of a buffer such as acetate, citrate, phosphate, succinate, Tris or histidine, typically employed in the range from about ImM to 5OmM.
  • the pH of compositions can otherwise be adjusted by using physiologically acceptable acids or bases.
  • Isotonicizing agents include sugar alcohols such as glycerol, mannitol or sorbitol; glucose; physiological salts such as sodium, potassium, magnesium or compounds such as NaCl, MgCl 2 or CaCl 2 .
  • Preservatives are generally included in pharmaceutical compositions to retard microbial growth, extending the shelf life of the compositions and allowing multiple use packaging.
  • preservatives include phenol, meta-cresol, benzyl alcohol, para-hydroxybenzoic acid and its esters, methyl paraben, propyl paraben, benzalconium chloride and benzethonium chloride.
  • Preservatives are typically employed in the range of about 0.1 to 1.0 % (w/v) .
  • the pharmaceutically compositions are given to an individual in a "prophylactically effective amount” or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy) , this being sufficient to show benefit to the individual. Typically, this will be to cause a therapeutically useful activity providing benefit to the individual .
  • the actual amount of the compounds administered, and rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners .
  • compositions are preferably administered to patients in dosages of between about 0.01 and lOOmg of active compound per kg of body weight, and more preferably between about 0.5 and 10mg/kg of body weight .
  • composition may further comprise one or more other pharmaceutically active agents, in particular further compounds for the treatment of the condition.
  • the medicaments can be administered simultaneously or sequentially with chemotherapy or radiotherapy .
  • the combinations of the present invention may be used to treat conditions which respond to the apoptosis-inducing effect of sigma ligands. In some cases, such conditions are characterised by activation of the IKK/NF-KB pathway.
  • NF-KB Activated NF-KB is proposed to play a role in both chronic and acute inflammation (Baldwin 1996 Annu Rev Immunol VoI 14 pp649-681) .
  • NF-KB is activated in arthritic synovium and anti-arthritic therapies block NF- ⁇ B activation.
  • Acute inflammation such as septic shock is also associated with NF- ⁇ B activation.
  • a number of chronic diseases are not obviously inflammatory in nature, but inflammatory mechanisms may play a part.
  • autoimmune diseases such as systemic lupus erythematosus, atherosclerosis and Alzheimer's disease are all reported to be associated with NF-KB activation.
  • Haslett (1997 British Medical Bulletin VoI 53 pp669-683) discovered that inflammatory cells undergo apoptosis constitutively and proposed that elimination of inflammatory cells by apoptosis is a crucial mechanism to limit the inflammatory response and that a failure of this mechanism leads to persistent inflammation.
  • An inappropriate NF- ⁇ B mediated drive to survive in chronic inflammation which is apparent through the extended average life span of inflammatory cells, leads to a loss of selective pressure to maintain alternative survival pathways over successive inflammatory cell generations .
  • Inflamed cells under these conditions become locked into a dependence on one pathway for survival, in an analogous way to tumour cells.
  • the combinations of the present invention combat this effect in a two-pronged attack, both by engaging the IKK/NF- ⁇ B pathway in a pro-apoptotic mode and by inhibiting the anti-apoptotic arm of the IKK/NF-KB pathway.
  • treatment includes any measure taken by the physician to alleviate the effect of the tumour on a patient.
  • effective treatment will also include any measures capable of achieving partial remission of the tumour as well as a slowing down in the rate of growth of a tumour including metastases .
  • Such measures can be effective in prolonging and/or enhancing the quality of life and relieving the symptoms of the disease.
  • Dosing is dependent on severity and responsiveness of the condition to be treated, with course of treatment lasting from several days to several months or longer until a diminution of disease state is achieved. Optimal dosing schedules are easily calculated from measurements of drug accumulation in the body. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Therapeutically or prophylactically effective amounts (dosages) may vary depending on the relative potency of individual compositions, and can generally be routinely calculated based on molecular weight and EC50s in in vitro and/or animal studies.
  • a dose in mg/kg is routinely calculated.
  • dosage is from 0.001 mg/kg to 100 mg/kg, for example 0.001 mg/kg, 0.01 mg/kg, 0.1 mg/kg, 1 mg/kg, 10 mg/kg or 100 mg/kg.
  • the dosage may be administered once or several times daily, weekly, monthly or yearly, or even every 2 to 20 years.
  • Rimcazole induces cell death through activation of NF-KB
  • NF-KB pathway activation is reduction in the level of the inhibitory protein I-KB that under non- stimulated conditions retains the ReIA (p65) subunit of NF-KB within the cytoplasm.
  • NF- ⁇ B-activating stimulus 1- ⁇ B is targeted for destruction either by the proteasome or by other means; this frees ReIA to move to the nucleus to exert either transactivation ortransrepression functions at NF- ⁇ B-dependent gene targets, the outcome of which may be either cell death or cell survival .
  • FIG. 1 shows a decline in 1- ⁇ B protein levels after 2, 4 and 24 hours of exposure to rimcazole in HL- 60 (acute promyelocytic leukaemia) cells and OPM-2 (multiple myeloma) cells.
  • NF-KB has been activated as a transcription factor
  • ESA electrophoretic mobility shift assay
  • Figure 2 exemplifies EMSA in H1299 lung cancer cells following exposure to rimcazole; a known activator of NF-KB, tumour necrosis factor (TNF) was used as a positive control.
  • Control cells display a basal level of DNA binding, indicative of constitutive NF-KB pathway activation in these cells.
  • RNA interference RNA interference
  • RelA knockdown substantially enhanced viable cell number in rimcazole-treated cells, compared with rimcazole-treated cells in which RelA levels were maintained by control, non-targeting RNAi ( Figure 3) . This confirms that rimcazole is able to provide a pro- apoptotic switch to the ReIA (p65) subunit of NF-kappaB.
  • rimcazole-induced cell death was substantially attenuated by a compound, JSH-23 (Shin et al 2004 FEBS Lett. Vol. 571 pp50) , that inhibits nuclear translocation and DNA binding of the NF-kappaB subunit ReIA (p65) . This confirms a requirement for activation of the NF-* B pathway in rimcazole-induced cell death ( Figure 4) .
  • Rimcazole-mediated death and growth inhibition in myeloid leukaemia cells is dependent on activity of NF- ⁇ B
  • HL60 acute promyelocytic leukaemia cells
  • plasmid vector encoding a super-repressor form of the I- ⁇ B protein (so-called double serine mutant at residues 32 and 36) or with parent vector (pcDNA3) alone then exposed to rimcazole at a range of concentrations .
  • Overexpression of the inhibitor protein I-KB is well recognised in the art as a method of inhibiting activation of the NF-KB pathway in living cells.
  • Figure 5 represents a graph of viable cell number over time, assayed using the MTS assay which is fully described in Spruce et al . , 2004 Cancer Research Vol. 64 pp4875-4886) .
  • Rimcazole reveals a pro-apoptotic switch in cells driven to survive through the NF-KB pathway HL60 cells were exposed to rimcazole in the presence and absence of the chemical BAY 11-7082, well known in the art as an inhibitor of IKK which is required for phosphorylation and thence degradation of the I- ⁇ B protein. IKK inhibitors are therefore known as inhibitors of the NP- ⁇ B pathway.
  • an assay for viable cell number over time was used to determine cell proliferation (net gain in viable cell number overtime) as well as cell death (net loss in viable cell number over time) ( Figure 6) .
  • the IKK inhibitor BAY 11-7082 (at 5 micromolar) caused cell death; this is consistent with a reliance of HL-60 cells upon an NF- ⁇ B-mediated survival drive that when removed is sufficient to cause cell death. Reliance of at least some leukaemic cells upon NF- ⁇ B for survival has been reported several times previously and is therefore well known in the art. Similarly, 12.5 micromolar rimcazole on its own caused decisive cell death after exposure for 72 hours. When rimcazole and BAY-11-7082 were combined, however, there was a substantial attenuation of cell death (open square symbols and dotted lines) .
  • IKK inhibition attenuates rimcazole-induced death and growth inhibition
  • HL60 cells were exposed to rimcazole in the presence and absence of a chemical inhibitor of IKK, parthenolide .
  • the IKK complex- involved in NF ⁇ B activation - consists of three core subunits - IKKl and IKK2 (also known as IKKalpha and iKKbeta, respectively) together with a third subunit, NEMO or IKKgamma.
  • IKK2 is the predominant IKB kinase in the canonical or classical pathway of NF-KB activation (Pasparakis et al . , 2006 Cell Death and Differentiation Vol. 13 pp861-872) .
  • Activation of IKK2 IKKbeta
  • IKKbeta typically stimulates anti-apoptotic, pro-inflammatory and proliferative pathways (Luo et al . , 2005 Journal of
  • SC-514 is also an inhibitor of IKK2 (Kishore et al . , 2003 J. Biol. Chem. Vol. 278, pp32861-32871) .
  • IKK2 Kishore et al . , 2003 J. Biol. Chem. Vol. 278, pp32861-32871
  • SC-514 caused a decline in viable cell number, confirming the existence of a constitutive, pro-survival drive mediated through IKK2.
  • SC-514 substantially preserved viable cell number ( Figure 9) . This provides further evidence for active engagement of IKK2 in a pro- death mode by rimcazole.
  • Rimcazole synergises with the proteasome inhibitor MG132 to enhance death induction in myeloid leukaemia cells
  • the proteasome inhibitor MG132 is known in the art as an NF-KB pathway inhibitor. The anticipation therefore was that combining rimcazole with MG132 would lead to an attenuation of cell death due to inhibition of an NF- ⁇ B- mediated pro-apoptotic drive.
  • HL60 cells treated with sublethal concentrations of rimcazole or MG132 as single agents there was some slowing of cell proliferation; however, when the agents were combined there was a decisively lethal effect (Figure 10) .
  • MG132 Synergy was also seen when cells were preincubated with MG132 for periods of up to 4 hours, prior to rimcazole addition. Lower concentrations of MG132 either had a lesser or no cooperative effect with rimcazole. Notably, MG132 consistently failed to reveal rescue from death in rimcazole- exposed cells as was seen with IKK inhibitors . From this it could be concluded that MG132 is acting in a substantially different way from the IKK inhibitors by enhancing rather than attenuating death induction and growth inhibition. Unlike IKK inhibitors, MG132 and similar agents may be useful as agents with which to combine rimcazole in order to enhance the efficacy of treatment for hematological malignancies including acute myeloid leukaemia.
  • Rimcazole synergises with the proteasome inhibitor bortezomib (PS-341, Velcade) to enhance cell death.
  • AML and solid tumour cells exposed to rimcazole and bortezomib in combination were killed significantly more effectively than when cells were exposed to either drug on its own. ( Figure 14) . This indicates the potential for rimcazole to have a dose-sparing effect when used in combination with therapeutics that have dose-related side-effects .
  • Rimcazole-induced reduction in IKB protein is independent of the proteasome As represented in Figure 1 above, rimcazole causes a reduction in IKB protein levels, consistent with activation of the NF- ⁇ B pathway. Typically, a reduction in IKB due to IKK activation is due to proteasome-mediated degradation. To determine involvement of the proteasome, HL60 cells were treated with rimcazole in the presence and absence of the proteasome inhibitor MG132 and subjected to immunoblotting (Figure 11) . This confirmed a reduction in IKB protein levels (compared to the loading control, actin, shown in the lower lanes) .
  • Rimcazole synergises with MG132 to enhance death in solid tumour cells
  • NF-KB driven tumours include estrogen receptor (ER) negative, aggressive breast cancers and glioblastoma, a malignant brain tumour type.
  • ER estrogen receptor
  • glioblastoma a malignant brain tumour type.
  • Cell lines representative of these two tumour types (MDA MB 231 and ul18MG, respectively) were treated with rimcazole and MG132 in combination as for acute myeloid leukaemia cells ( Figures 12 and 13) . In both cases, cells were grown at high density to reduce cell killing in response to rimcazole or MG132 alone.
  • MDA MB 231 and U118MG cells In the presence of either rimcazole or MG132 alone, MDA MB 231 and U118MG cells not only remained viable but proliferated at rates that were close to those of control cells (exposed to drug vehicle alone) . However, in the combined presence of rimcazole and MG132, cells were killed decisively. This confirms a synergistic effect in representative solid tumour types that are paradigms of IKK/NF-KB deregulation. This indicates the potential for a combination of rimcazole, or another sigma ligand, with MG132, or a similar agent, to enhance therapeutic efficacy in solid tumour types .
  • MG132 is well known in the art as an NF-KB pathway inhibitor. It was therefore surprising that MG132 enhanced cell death in response to rimcazole as this was in clear contrast to other NF-KB pathway inhibitors, such as IKK inhibitors, that attenuate rather than enhance cell death in response to rimcazole. Given that the proteasome is downstream from IKK in the NF-KB pathway we reasoned that IKK may be responsible for activation of anti- and pro-apoptotic arms of the NF-KB pathway but that the proteasome may be specifically involved in an IKK-dependent, anti-apoptotic function of NF-KB.
  • a proteasome inhibitor such as MG132 could potentially synergise with rimcazole due to selective inhibition of an anti- apoptotic arm of NF-KB function while leaving a pro-apoptotic arm unchecked.
  • leukaemia and solid tumour cell lines were treated with a triple combination of MG132 and rimcazole together with an IKK inhibitor. Synergistic death induction was demonstrated, as above, by the combination of MG132 and rimcazole; however, this was substantially reversed in the presence of BAY 11-7082 in leukaemia (HL- 60 cells, Figure 15) and ER negative breast cancer (MDA MB 231 cells, Figure 16) .
  • parthenolide partially restored cell viability to acute myelocytic leukaemia cells that had been treated with rimcazole and MG132 (HL- 60 cells, Figure 17) .
  • MG132 selectively inhibits an anti-apoptotic arm of IKK/NF-KB function, allowing rimcazole to remain unopposed in its engagement of IKK in pro-apoptotic mode.
  • the combination of rimcazole, or other sigma ligands, with MG132, or similar agents within the class will be useful in treating a broad range of malignancies and inflammatory disease where deregulated pro- survival and pro-proliferation functions of IKK are implicated in driving the disease.
  • Rimcazole synergises with a subset of HDAC inhibitors that selectively inhibit an anti-apoptotic arm of NF-KB function
  • NF-KB pathway activators As outlined above, the combination of rimcazole and other sigma ligands with the subset of HDAC inhibitors that are known in the art as NF-KB pathway activators has been disclosed in essence in WO 00/00599. It is also known that some HDAC inhibitors have an opposite effect of NF-KB pathway inhibition, such as the exemplary agent sodium valproate (otherwise known as valproic acid) . It was reasoned that if valproate is a selective inhibitor of an anti-apoptotic arm of IKK/NF-KB pathway function it would be expected to enhance rather than attenuate rimcazole 's cell death-inducing effect.
  • sodium valproate selectively inhibits stimulated or constitutive iKK-dependent anti- apoptotic and pro-proliferative functions, leaving rimcazole unchecked in its IKK-dependent , pro-apoptotic and growth inhibitory functions .
  • Non small cell lung cancer cells are known to express the wild-type (non-mutant) form of the EGF receptor (Das et al., 2006 Cancer Res 66:9601-9608) .
  • the inventors have shown that when H1299 cells are exposed in culture to rimcazole in combination with the EGFR inhibitor gefitinib (Iressa) there is a marked reduction on viable cell number ( Figure 22) that was significantly greater than the sum of the effect following exposure to each drug alone.
  • Gefitinib is known in the clinic as an agent that is effective in treating a minority of patients with non small cell lung cancer. It is also known to be less effective in patients who carry the wild-type form of the EGF receptor who are therefore resistant to gefitinib (Lynch et al., 2004 NEJM 350: 2129- 2139; Paez et al., 2004 Science 304 (5676) : 1497-1500) .
  • H1299 lung cancer cells are also known to be gefitinib resistant, consistent with expression of the wild type EGFR (Engelman et al., 2005 PNAS 102(10) : 3788-3793) . We show herein that H1299 cells become substantially more susceptible to gefitinib (Iressa) when used in combination with rimcazole. Rimcazole is therefore of particular use to overcome resistance to gefitinib in lung cancer patients .
  • ER negative breast cancer cells in particular also express high levels of the EGFR, including MDA MB 468 cells in which the EGFR gene is amplified (Filmus et al., 1987 MoI Cell Biol 7(1) : 251-257) .
  • MDA MB 468 cells were exposed to rimcazole and gefitinib (Iressa) in combination, there was a synergistic effect such that the reduction in viable cell number was greater than the sum of the effect with each drug alone ( Figure 23) .
  • rimcazole is of use in combination with EGFR inhibitors to treat a range of EGFR- expressing tumours, including those that are resistant to EGFR inhibitors .

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Abstract

La présente invention concerne des agents qui agissent de concert avec des ligands des récepteurs sigma pour amplifier leur efficacité dans le traitement d'un cancer et d'une maladie inflammatoire. L'invention a également pour objet des procédés par lesquels il est possible d'identifier des agents qui seront utiles en combinaison avec des ligands des récepteurs sigma dans le traitement desdites maladies.
PCT/GB2008/004109 2007-12-13 2008-12-12 Ligands des récepteurs sigma et inhibiteurs d'ikk / nf-kb pour traitement médical Ceased WO2009074809A1 (fr)

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WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication
WO2017106312A1 (fr) * 2015-12-18 2017-06-22 Drexel University Méthodes de modulation de niveaux d'il-6 et de pd-l1
WO2018156883A1 (fr) * 2017-02-23 2018-08-30 Board Of Regents, The University Of Texas System Méthodes de traitement du cancer, d'homéostasie des stérols et de maladies neurologiques
CN111670183A (zh) * 2017-08-07 2020-09-15 Biocad股份公司 作为cdk8/19抑制剂的新型杂环化合物
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
WO2023120963A1 (fr) * 2021-12-21 2023-06-29 한국과학기술연구원 Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon comprenant un composé dérivé de carbazole en tant que principe actif
WO2025031979A1 (fr) 2023-08-04 2025-02-13 Kyrexa Ltd Utilisation du rimcazole pour traiter le cancer
US12398108B2 (en) 2017-11-01 2025-08-26 Drexel University Compounds, compositions, and methods for treating diseases

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058166A1 (fr) * 2008-11-18 2010-05-27 Modern Biosciences Plc Utilisation du rimcazole pour le traitement de troubles oculaires
US11873266B2 (en) 2012-05-08 2024-01-16 Aeromics, Inc. Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke
US11084778B2 (en) 2012-05-08 2021-08-10 Aeromics, Inc. Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
WO2015037659A1 (fr) 2013-09-13 2015-03-19 株式会社医薬分子設計研究所 Préparation de solution aqueuse et son procédé de fabrication
US9974860B2 (en) 2013-09-13 2018-05-22 Akiko Itai Aqueous solution formulation and method for manufacturing same
US10894055B2 (en) 2013-11-06 2021-01-19 Aeromics, Inc. Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
US11071744B2 (en) 2013-11-06 2021-07-27 Aeromics, Inc. Prodrug salts
US11801254B2 (en) 2013-11-06 2023-10-31 Aeromics, Inc. Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
US12213987B2 (en) 2013-11-06 2025-02-04 Aeromics, Inc. Prodrug salts
WO2017106312A1 (fr) * 2015-12-18 2017-06-22 Drexel University Méthodes de modulation de niveaux d'il-6 et de pd-l1
WO2018156883A1 (fr) * 2017-02-23 2018-08-30 Board Of Regents, The University Of Texas System Méthodes de traitement du cancer, d'homéostasie des stérols et de maladies neurologiques
CN111670183A (zh) * 2017-08-07 2020-09-15 Biocad股份公司 作为cdk8/19抑制剂的新型杂环化合物
US12398108B2 (en) 2017-11-01 2025-08-26 Drexel University Compounds, compositions, and methods for treating diseases
WO2023120963A1 (fr) * 2021-12-21 2023-06-29 한국과학기술연구원 Composition pharmaceutique pour la prévention ou le traitement du cancer du poumon comprenant un composé dérivé de carbazole en tant que principe actif
WO2025031979A1 (fr) 2023-08-04 2025-02-13 Kyrexa Ltd Utilisation du rimcazole pour traiter le cancer

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