WO2004093871A1 - Novel methods for the treatment of cancer - Google Patents

Novel methods for the treatment of cancer Download PDF

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Publication number
WO2004093871A1
WO2004093871A1 PCT/US2004/005155 US2004005155W WO2004093871A1 WO 2004093871 A1 WO2004093871 A1 WO 2004093871A1 US 2004005155 W US2004005155 W US 2004005155W WO 2004093871 A1 WO2004093871 A1 WO 2004093871A1
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Prior art keywords
carboline
ido
inhibitor
methyl
tryptophan
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PCT/US2004/005155
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English (en)
French (fr)
Inventor
George C. Prendergast
Alexander J. Muller
James B. Duhadaway
William Malachowski
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Lankenau Institute for Medical Research
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Lankenau Institute for Medical Research
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Priority to JP2006508789A priority Critical patent/JP4921965B2/ja
Priority to EP10075396.1A priority patent/EP2260846B1/en
Priority to US10/551,151 priority patent/US8008281B2/en
Priority to EP04713378A priority patent/EP1613308A4/en
Priority to CA2520172A priority patent/CA2520172C/en
Priority to CN200480014321.1A priority patent/CN1794986B/zh
Publication of WO2004093871A1 publication Critical patent/WO2004093871A1/en
Anticipated expiration legal-status Critical
Priority to US13/186,848 priority patent/US8383613B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
    • C07D517/04—Ortho-condensed systems

Definitions

  • This invention relates to the fields of oncology and chemotherapy. Specifically, the invention provides novel methods for the treatment of cancer.
  • Tumors characteristically express atypical, potentially immunoreactive antigens that are collectively referred to as tumor antigens. Accumulating evidence suggests that the failure of the immune system to mount an effective response against progressively growing tumors is not attributable to a lack of recognizable tumor antigens. Immunosuppression by tumors is poorly understood and mechanisms by which tumors may escape immune surveillance are poorly explored. Recently, it has been shown that cytotoxic T cells become tolerized by a reduction in local concentrations of tryptophan that are elicited by indoleamine 2 , 3-dioxygenase (IDO) activity.
  • IDO 3-dioxygenase
  • IDO is an oxidoreductase that catalyzes the rate-limiting step in tryptophan catabolism. This enzyme is structurally distinct from tryptophan dioxygenase (TDO) , which is responsible for dietary tryptophan catabolism in the liver. IDO is an IFN- ⁇ target gene that has been suggested to play a role in immunomodulation (Mellor and Munn (1999) Immunol. Today. 20:469-473). Elevation of IDO activity depletes the levels of tryptophan in local cellular environments. Induction of IDO in antigen-presenting cells, where IDO is regulated by IFN- ⁇ , blocks the activation of T cells, which are especially sensitive to tryptophan depletion. T cells must undergo 1-2 rounds of cell division to become activated, but in response to tryptophan depletion they arrest in GI instead. In this way, IDO has been proposed to inhibit the T H 1 responses that promote cytotoxic T cell development.
  • a method for treating a cancer in a patient in need thereof by administering a therapeutically effective amount of at least one compound that has been discovered to have IDO inhibitory activity in accordance with this invention.
  • the compounds may be administered in a pharmaceutically acceptable carrier medium.
  • a method is provided for treating a cancer in a patient in need thereof by administering to the patient, concurrently or sequentially, a therapeutically effective amount of at least one indoleamine 2 , 3-dioxygenase (IDO) inhibitor and at least one signal transduction inhibitor (STI) .
  • IDO indoleamine 2
  • STI signal transduction inhibitor
  • a method for treating a chronic viral infection in a patient in need thereof by administering to the patient, concurrently or sequentially, a therapeutically effective amount of at least one indoleamine 2 , 3-dioxygenase (IDO) inhibitor and at least one chemotherapeutic agent.
  • IDO 3-dioxygenase
  • the treated chronic viral infection is selected from the group consisting of: hepatitis C virus (HCV) , human papilloma virus (HPV) , cytomegalovirus (CMV) , Epstein- Barr virus (EBV) , varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV) .
  • the compounds may be administered in a pharmaceutically acceptable carrier medium.
  • a “signal transduction inhibitor” is an agent that selectively inhibits vital step(s) in signaling pathways, in the normal function of cancer cells, and thereby leading to apoptosis.
  • Signal transduction inhibitors include, but are not limited to, (i) bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) and derivatives thereof; (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (Iressa, SSI-774) and antibodies (Imclone: C225 [Goldstein et al . (1995), Clin Cancer Res .
  • bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) and derivatives thereof
  • epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (Iressa, SSI-774) and antibodies (Imclone: C225 [Goldstein et al . (1995), Clin Cancer Res .
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • “Sequentially” refers to the administration of one active agent used in the method followed by administration of another active agent. After administration of one active agent, the next active agent can be administered substantially immediately after the first, or the next active agent can be administered after an effective time period after the first active agent; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first active agent.
  • the present invention provides a method for the treatment of cancer by administering to a patient, in need thereof, a therapeutically effective amount of at least one of the IDO inhibitors mentioned immediately above .
  • Cancers that may be treated using the present protocol include, but are not limited to: cancers of the prostate, colorectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma) , mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell carcinoma) , adrenal gland, thyroid, kidney, or bone; glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma.
  • Suitable STIs include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec) and derivatives thereof; (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (Iressa, SSI-774) and antibodies (Imclone: C225 [Goldstein et al . (1995), Clin Cancer Res . 1:1311-1318], and Abgenix: ABX-EGF) ; (iii) her-2/neu receptor inhibitors such as, for example, HerceptinTM
  • Akt family kinases or the Akt pathway such as, for example, rapamycin (see, for example, Sekulic et al . (2000) Cancer Res. 60:3504- 3513);
  • cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-01 (see, for example, Sausville (2003) Curr. Med. Chem.
  • the at least one IDO inhibitor may be selected from compounds of the group consisting of: i) compounds previously established to exhibit IDO inhibitory properties including, but not limited to: 1-methyl-DL- tryptophan (IMT), ⁇ - (3 -benzofuranyl) -DL-alanine, beta- (3- benzo (b) thienyl) -DL-alanine, 6-nitro-L-tryptophan, indole 3 -carbinol , 3,3' -diindolylmethane , epigallocatechin gallate, 5-Br-4-Cl-indoxyl 1, 3-diacetate, 9- vinylcarbazole, acemetacin, 5-bromo-DL-tryptophan, 5- bromoindoxyl diacetate, brassilexin, 3-amino-2naphthoic acid, ⁇ -carboline, 3 -butyl - ⁇ -carboline, 6-fluoro-3- carbomethoxy- ⁇ -carbol
  • the group of IDO inhibitors may additionally include compounds discovered to have IDO inhibitory activity, in accordance with the present invention, and previously identified as anti-tumor agents, including, but not limited to brassinin, 5-methyl-brassinin, 3,3'- diindolylmethane (DIM) , and indole-3 -carbinol (I3C) .
  • the at least one IDO inhibitor and at least one STI may be administered to the patient concurrently or sequentially.
  • the at least one IDO inhibitor may be administered first, the at least one STI may be administered first, or the at least one IDO inhibitor and the at least one STI may be administered at the same time.
  • the compounds may be administered in any order. Cancers that may be treated using the present combinatorial protocol include, but are not limited to those cancers described hereinabove .
  • the at least one IDO inhibitor may be selected from the group consisting of: i) known IDO inhibitors as previously described and ii) compounds discovered to have IDO inhibitory activity, in accordance with this invention, also previously described herein.
  • the group of IDO inhibitors may additionally include compounds discovered to have IDO inhibitory activity, in accordance with the present invention, and previously identified as anti-tumor agents, including, but not limited to brassinin, 5- methyl-brassinin, 3 , 3 ' -diindolylmethane (DIM), and indole-3-carbinol (I3C) .
  • the present invention also provides a method for treating a chronic viral infection by a combination protocol comprising administration of an IDO inhibitor with a chemotherapeutic agent. Additionally, the method also comprises administering an antiviral agent (i.e., an agent which can treat a viral infection) in coordination with the IDO inhibitor and chemotherapeutic agent. Accordingly, the present invention provides a pharmaceutical composition for the treatment of a chronic viral infection in a patient comprising at least one IDO inhibitor, at least one cancer therapeutic drug in a pharmaceutically acceptable carrier, and, optionally, at least one antiviral agent. Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of at least one IDO inhibitor in combination with at least one chemotherapeutic agent and, optionally, at least one antiviral agent.
  • an antiviral agent i.e., an agent which can treat a viral infection
  • the at lea'st one IDO inhibitor may be selected from the group consisting of: i) known IDO inhibitors as previously described and ii) compounds discovered to have IDO inhibitory activity, in accordance with this invention, also previously described herein.
  • the group of IDO inhibitor may additionally include compounds discovered to have IDO inhibitory activity, in accordance with the present invention, and previously identified as anti-tumor agents, including, but not limited to brassinin, 5- methyl-brassinin, 3 , 3' -diindolylmethane (DIM), and indole-3-carbinol (I3C) .
  • the chemotheraputic agent is selected from the group consisting of: paclitaxel (Taxol ® ), cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11, 5-fluorouracil (5-FU) , gemcitabine, estramustine, carmustine, adriamycin (doxorubicin) , etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
  • paclitaxel Tixol ®
  • cisplatin docetaxol
  • carboplatin carboplatin
  • vincristine vinblastine
  • methotrexate methotrexate
  • cyclophosphamide CPT-11
  • 5-fluorouracil 5-fluorouracil
  • gemcitabine gemcitabine
  • estramustine carmustine
  • compositions of the present invention can be administered by any suitable route, for example, by injection, by oral, pulmonary, nasal or other methods of administration.
  • pharmaceutical compositions of the present invention comprise, among other things, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.
  • compositions can include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate) , pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite) , preservatives (e.g., Thimersol , benzyl alcohol) and bulking substances (e.g., lactose, mannitol) .
  • the compositions can be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes.
  • compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of a pharmaceutical composition of the present invention. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, PA 18042) pages 1435-1712 which are herein incorporated by reference.
  • the pharmaceutical composition of the present invention can be prepared, for example, in liquid form, or can be in dried powder form (e.g., lyophilized) . Particular methods of administering pharmaceutical compositions are described hereinabove .
  • the enzymatic assay provides a facile, high-throughput screen for identifying compounds with IDO inhibitory activity. This assay is also used to determine Ki values for specific compounds, which is important for the development of SAR (structure activity relationship) around the different compound series.
  • the cell-based assay both confirms the IDO inhibitory activity of identified compounds, and addresses the initial issue of bioavailability - the ability of compounds to inhibit intracellular IDO. Specificity for IDO inhibition is examined in the cell-based assay by comparing against the other known tryptophan catabolizing enzyme tryptophan dioxygenase (TDO, also referred to in the literature as TD02) .
  • TDO tryptophan catabolizing enzyme tryptophan dioxygenase
  • cDNA clones for both human and mouse IDO have been isolated and verified by sequencing.
  • C-terminal His- tagged IDO protein can be produced in E. coli using the IPTG-inducible pET5a vector system and isolated over a nickel column. The yield of the partially purified protein can be verified by gel electrophoresis and the concentration estimated by comparison to protein standards.
  • a 96-well plate spectraphotometric assay for kynurenine production can be run following published procedures (LittleJohn, T.K., et al. (2000) Prot . Exp . Purif. 19:22-29; Takikawa, 0., et al .
  • L-744,832 which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of farnesyl transferase (FTI) (Kohl et al . , (1995) Nat Med. 1 (8) : 747-748) .
  • FTI farnesyl transferase
  • the time-release pellets are comprised of a copolymer which is inert and gradually dissolves and breaks down to a non-toxic substance that remains largely localized during the course of the experiment. Time-release pellets impregnated with IMT release a dose of 10 mg/day for a period of up to 14 days as documented by the commercial vendor (Innovative Research, Inc., Sarasota, FL) .
  • 293/Phoenix cells were transiently transfected with human IDO or TDO cDNA expression vectors.
  • the candidate compounds were added to the transfected cells at various concentrations.
  • Kynurenine was quantitated in tissue culture media using a fluorescence-based protocol . The results from these experiments are presented in Figures 7-9.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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PCT/US2004/005155 2003-03-27 2004-02-20 Novel methods for the treatment of cancer Ceased WO2004093871A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2006508789A JP4921965B2 (ja) 2003-03-27 2004-02-20 癌治療新規方式
EP10075396.1A EP2260846B1 (en) 2003-03-27 2004-02-20 Novel methods for the treatment of cancer
US10/551,151 US8008281B2 (en) 2003-03-27 2004-02-20 Methods for the treatment of cancer
EP04713378A EP1613308A4 (en) 2003-03-27 2004-02-20 NEW METHODS OF TREATING CANCER
CA2520172A CA2520172C (en) 2003-03-27 2004-02-20 Novel methods for the treatment of cancer with an indoleamine 2, 3-dioxygenase inhibitor
CN200480014321.1A CN1794986B (zh) 2003-03-27 2004-02-20 治疗癌症的新药物
US13/186,848 US8383613B2 (en) 2003-03-27 2011-07-20 Methods for the treatment of cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45816203P 2003-03-27 2003-03-27
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EP1613308A4 (en) 2008-02-20
CA2520586C (en) 2011-06-14
WO2004094409A1 (en) 2004-11-04
US20100233166A1 (en) 2010-09-16
CA2520172C (en) 2012-10-02
EP1606285A4 (en) 2009-03-18
EP2260846B1 (en) 2018-11-28
JP2006521377A (ja) 2006-09-21
US20110311648A1 (en) 2011-12-22
EP1613308A1 (en) 2006-01-11
US8476454B2 (en) 2013-07-02
JP2006521378A (ja) 2006-09-21
CA2520586A1 (en) 2004-11-04
JP4921965B2 (ja) 2012-04-25
EP2260846A1 (en) 2010-12-15
CA2520172A1 (en) 2004-11-04
US7714139B2 (en) 2010-05-11
US20070099844A1 (en) 2007-05-03
EP1606285A1 (en) 2005-12-21
US8383613B2 (en) 2013-02-26
US8008281B2 (en) 2011-08-30

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