WO2008033807A2 - Combinaisons synergiques d'oxydants mitochondriaux antinéoplasiques se liant au thiol et d'inhibiteurs du protéasome antinéoplasiques pour le traitement du cancer - Google Patents

Combinaisons synergiques d'oxydants mitochondriaux antinéoplasiques se liant au thiol et d'inhibiteurs du protéasome antinéoplasiques pour le traitement du cancer Download PDF

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WO2008033807A2
WO2008033807A2 PCT/US2007/078119 US2007078119W WO2008033807A2 WO 2008033807 A2 WO2008033807 A2 WO 2008033807A2 US 2007078119 W US2007078119 W US 2007078119W WO 2008033807 A2 WO2008033807 A2 WO 2008033807A2
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antineoplastic
combination
thiol
cancer
binding mitochondrial
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PCT/US2007/078119
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WO2008033807A3 (fr
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Robert T. Dorr
David S. Alberts
Evan M. Hersh
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The Arizona Board Of Regents On Behalf Of The University Of Arizona
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    • 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
    • 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
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • 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

Definitions

  • This disclosure relates generally to methods and compositions for the treatment of cancer, and more particularly, to synergistic combinations of an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor.
  • cancer is a leading cause of death in humans and animals. As such, considerable resources are invested in the discovery and clinical investigation of therapies that may be effective in treating the many forms of cancer.
  • cancer therapies employ combinations of chemotherapeutic agents in the hope of achieving a more beneficial therapeutic result.
  • some drugs interact with each other to reduce the therapeutic effectiveness or cause undesired side-effects. These drugs are typically categorized as having an antagonistic effect.
  • Other drug combinations manifest their therapeutic effectiveness as the sum of the individual drugs. These combinations are categorized as having an additive effect.
  • Still other drug combinations result in a therapeutic index that is greater than the sum of the individual drugs. These combinations are categorized as having a synergistic effect.
  • Combination therapies having a synergistic effect are highly desirable for many reasons.
  • each component in a synergistic combination therapy can be used in an amount lower than the therapeutic amount of each individual drug in monotherapy (i.e., single drug administration).
  • the risk and/or the severity of side-effects can be reduced significantly by reducing the amount of each drug.
  • combination therapy may significantly increase the overall effectiveness of treatment.
  • finding combinations of drugs with synergistic effect is largely empirical.
  • the present invention is directed to methods and compositions useful in the treatment of cancer. It has been discovered that, surprisingly, the combination of an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor is synergistic when used in the treatment of cancer.
  • the present invention provides a method for treating cancer in a human patient in need of such treatment.
  • the method includes administering to the patient a therapeutically effective amount of an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor.
  • the amount provides a synergistic therapeutic cytotoxic effect.
  • the present invention provides a combination having therapeutic synergy in the treatment of cancer, wherein the combination comprises an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor.
  • the present invention provides a use of an antineoplastic thiol- binding mitochondrial oxidant and an antineoplastic proteasome inhibitor in the manufacture of a medicament to treat cancer, wherein the antineoplastic thiol-binding mitochondrial oxidant and the antineoplastic proteasome inhibitor are administered simultaneously or concurrently to achieve a synergistic therapeutic cytotoxic effect.
  • the present invention provides a use of an antineoplastic thiol- binding mitochondrial oxidant in the manufacture of a medicament to treat cancer in combination with an antineoplastic proteasome inhibitor, wherein the combination has therapeutic synergy. Also provided is a use of an antineoplastic proteasome inhibitor in the manufacture of a medicament to treat cancer in combination with an antineoplastic thiol- binding mitochondrial oxidant, wherein the combination has therapeutic synergy.
  • cancer refers to all types of cancers, neoplasms, or malignant tumors found in mammels, including carcinomas, sarcomas, melanomas, leukemias, and lymphomas.
  • hematological malignancy refers to cancers affecting cells of the blood, bone marrow, and lymph nodes, and including without limitation multiple myeloma (also known as plasma cell neoplasia), leukemias, and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, Hodgkin's disease, chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, mediastinal large B
  • the term "antineoplastic” means inhibiting or preventing the growth of cancer. "Inhibiting or preventing the growth of cancer” includes reducing the growth of cancer relative to the absence of a given therapy or treatment. Cytotoxic assays useful for determining whether a compound is antineoplastic are discussed herein (see Assays for Testing the Anticancer Synergistic Activity of a Combination of an Antineoplastic Thiol- binding Mitochondrial Oxidant and a Second Antineoplastic Agent).
  • the terms "combination therapy” or "adjunct therapy” mean that a patient in need of the drag is treated with or given another drug for the disease in conjunction with an antineoplastic thiol-binding mitochondrial oxidant.
  • This combination therapy can be sequential therapy in which the patient is treated first with one drug and then the other, or the two drags can be administered to the patient simultaneously.
  • impexon refers to an unsubstituted 4-imino-l,3- diazabicyclo[3.1.0]-hexan-2-one, or a pharmaceutically acceptable salt or a solvate thereof.
  • the terms “synergistic therapeutic cytotoxic effect,” “therapeutic synergy,” and “synergistically therapeutic” mean that a specified combination of at least two compounds exhibit synergy when tested in a cytotoxic assay (see Assays for Testing the Anticancer Synergistic Activity of a Combination of an Antineoplastic Thiol-binding Mitochondrial Oxidant and a Second Antineoplastic Agent). Synergy is assessed using the median-effect principle (Chou et al, Adv. Enzyme Regul., 22: 27-55 (1984)). This method is based on Michaelis-Menton kinetics and reduces combination effects to a numeric indicator, the combination index ("CL").
  • a "pharmaceutially acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • the term "therapeutically effective amount” refers to the amount of a compound or composition effective to yield the desired therapeutic response.
  • the therapeutically effective amount may vary with such factors as the particular condition or clinical pattern of disease being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight ⁇ i.e. unbranched) or branched chain hydrocarbon radical which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C 1 -Ci O means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified, but not limited by, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), and isopropylene (-CH 2 (CH 3 )-CH 2 -).
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S- CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R 1 OC(O)-.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R" or the like, it will be understood that the terms heteroalkyl and -NR 1 R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR 1 R" or the like.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl 1-pyrrolidinyl, 2-pyrrolidinyl, and the like.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C 4 )alkyl is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-
  • arylene and heteroarylene refer to the divalent derivatives of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms ⁇ e.g. , aryloxo, arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like).
  • haloaryl as used herein, is meant to cover only aryls substituted with one or more halogens.
  • oxo as used herein means an oxygen that is double bonded to a carbon atom.
  • R 1 , R" and R'" each preferably independently refer to hydrogen, or C 1 -C 6 alkyl, cycloalkyl, or haloalkyl. Unless otherwise stated, when a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R" and R 1 " groups when more than one of these groups is present.
  • exemplary substituents for aryl and heteroaryl groups are varied and are selected from, for example: -OR 1 , -NR 1 R", -SR', -halogen, -OC(O)R 1 , -C(O)R', -CO 2 R', - C(O)NR 1 R", -OC(O)NR 1 R", -NR 11 C(O)R 1 , -NR'-C(0)NR"R"', -NR 11 C(O)OR 1 , -NR-OR 1 , -NR-OR 1 , -NR-OR 1 , -NR 1 R", -SR', -halogen, -OC(O)R 1 , -C(O)R', -CO 2 R', - C(O)NR 1 R", -OC(O)NR 1 R", -NR 11 C(O)R 1 , -NR'-C(0)NR"R"', -NR 11 C(O)OR 1 , -
  • Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 X-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(CR"R 1 ") d -, where s and d are independently integers of from O to 3, and X 1 is -O- , -NR 1 -, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR 1 -.
  • the substituents R, R 1 , R" and R 1 " is each independently selected from hydrogen, C 1 -C 6 alkyl, cycloalkyl, or haloalkyl.
  • heteroatom or “ring heteroatom” is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • the compounds of the present invention may exist as salts.
  • the present invention includes such salts. These salts may be prepared by methods known to those skilled in art.
  • pharmaceutically acceptable salts is meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et ah, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • a when used in reference to a group of substituents herein, mean at least one.
  • a compound when used in reference to a group of substituents herein, mean at least one.
  • the compound when used in reference to a group of substituents herein, mean at least one.
  • the compound when used in reference to a group of substituents herein, mean at least one.
  • the compound when used in reference to a group of substituents herein, mean at least one.
  • the compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R substituent where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • Combinations of antineoplastic agents in accordance with embodiments of the present invention exhibit a synergistic therapeutic cytotoxic effect in the treatment of cancer.
  • Synergistic combinations of the present invention include an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor.
  • the combinations of the present invention are useful in treating a wide variety of cancers.
  • synergistic combinations in accordance with the present invention are useful in treating hematological malignancies, including without limitation, multiple myeloma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphomas, Burkitt's lymphoma, and acute lymphoblastic leukemia.
  • the compounds and compositions described herein are useful in the preparation of medicaments to treat cancer.
  • the invention includes the use of an antineoplastic thiol- binding mitochondrial oxidant and an antineoplastic proteasome inhibitor in the manufacture of a medicament to treat cancer, wherein the antineoplastic thiol-binding mitochondrial oxidant and the antineoplastic proteasome inhibitor are administered simultaneously or concurrently to achieve a synergistic therapeutic cytotoxic effect.
  • the invention also includes the use of an antineoplastic thiol-binding mitochondrial oxidant in the manufacture of a medicament to treat cancer in combination with an antineoplastic proteasome inhibitor, wherein the combination has therapeutic synergy.
  • the invention includes the use of an antineoplastic proteasome inhibitor in the manufacture of a medicament to treat cancer in combination with an antineoplastic thiol-binding mitochondrial oxidant, wherein the combination has therapeutic synergy.
  • Antineoplastic thiol-binding mitochondrial oxidants in accordance with embodiments of the present invention are those compounds that inhibit or prevent the growth of cancer, are capable of binding a thiol moiety on a thiol-containing molecule, and promote oxidative stress and disrupt cellular mitochondrial membrane potential.
  • An antineoplastic thiol-binding mitochondrial oxidant typically induces gross alterations in mitochondrial ultrastructure (e.g., swelling), while inducing little or no alterations to other cellular organelles. Alterations in the mitochondrial ultrastructure is typically caused by inducation of oxidative stress to mitochondrial biomolecules, such as mitochondrial DNA.
  • ROS reactive oxygen species
  • the antineoplastic thiol-binding mitochondrial oxidant inhibits or reduces activity of a ribonucleotide reductase inhibitor (relative to the activity in the absence of an antineoplastic thiol-binding mitochondrial oxidant).
  • the antineoplastic thiol-binding mitochondrial oxidant does not alkylate DNA.
  • the antineoplastic thiol-binding mitochondrial oxidant does not react with the €-amino group of lysine.
  • antineoplastic thiol-binding mitochondrial oxidants in accordance with the present invention include an aziridine (see, e.g., the compounds of Formulae (I), (II), and (III)).
  • the presence of the aziridine ring is believed to enable the antineoplastic thiol-binding mitochondrial oxidant to bind cellular thiols, such as glutathione ("GSH") and cysteine residues within cellular proteins.
  • GSH glutathione
  • tumor cells become highly susceptible to oxidation.
  • the antineoplastic thiol-binding mitochondrial oxidant is a substituted or unsubstituted aziridine- 1-carboxamide having the formula:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 4 and R 5 are optionally joined together to form a substituted or unsubstituted 5 to 7 membered ring.
  • R 4 is cyano, CO 2 R 4A , or CONR 4B R 4C .
  • R 4A is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl.
  • R 4B is selected from hydrogen or substituted or unsubstituted alkyl.
  • R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl.
  • antineoplastic thiol-binding mitochondrial oxidant is a substituted or unsubstituted aziridine-1-carboxamide of Formula (I)
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, substituted or unsubstituted (C 1 -C 6 ) alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, substituted or unsubstituted 5 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 4 is selected from cyano, unsubstituted carboxamide or unsubstituted carboxylic acid ester.
  • R 5 is selected from hydrogen, substituted or unsubstituted (Ci-C 4 ) alkyl, and substituted or unsubstituted aryl.
  • the antineoplastic thiol-binding mitochondrial oxidant is a substituted or unsubstituted aziridine-1-carboxamide of Formula (I), R 4 and R 5 are joined together to form a substituted 5 membered ring.
  • the compound of Formula (I) is imexon.
  • the concentration of imexon in a composition is at least 0.5 ⁇ g/ml.
  • the concentration of imexon in a composition is at least 1.0 jug/ml
  • the concentration of imexon in a composition is between about 1.0 ⁇ g/ml and about 500 ⁇ g/ml.
  • the antineoplastic thiol-binding mitochondrial oxidant is selected from a substituted or unsubstituted 4-imino-l,3-diazabicyclo[3.1.0]- hexan-2-one and a substituted or unsubstituted aziridine-1-carboxamide.
  • Aziridine-1- carboxamides and cyclic derivatives thereof useful in accordance with the present invention are described in detail in U.S. Pat. No. 6,297,230 and U.S. Pat. No. 6,476,236, which are hereby incorporated by reference in their entirety for all purposes.
  • the antineoplastic thiol-binding mitochondrial oxidant is a substituted or unsubstituted 4-imino-l,3-diazabicyclo[3.1.0]-hexan-2-one having the formula:
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, substituted or unsubstituted (Ci-C 6 ) alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R , R 2 , and R 3 are independently selected from hydrogen and substituted or unsubstituted (Ci-C 6 ) alkyl. It will be appreciated that in one embodiment, when R 1 , R 2 , and R 3 are hydrogen, the compound of Formula (II) is imexon.
  • the antineoplastic thiol-binding mitochondrial oxidant is a substituted or unsubstituted aziridine-1-carboxamide having the formula:
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R 4 is selected from cyano, CO 2 R 4A and CONR 4B R 4C .
  • R 4A is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl.
  • R 4B is selected from hydrogen and substituted or unsubstituted alkyl.
  • R 4C is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted aryl.
  • R 5 is selected from hydrogen and substituted or unsubstituted alkyl.
  • R 6 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • the present invention is directed to pharmaceutical compositions and methods for the treatment of cancer comprising the combination administration of an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor. It has been discovered that, surprisingly, the combination of an antineoplastic thiol- binding mitochondrial oxidant and an antineoplastic proteasome inhibitor exhibits a synergistic therapeutic cytotoxic effect.
  • Antineoplastic proteasome inhibitors in accordance with embodiments of the present invention are those compounds that inhibit or prevent the growth of cancer and are capable of inhibiting the proteolytic activity of the 2OS proteasome in mammalian cells.
  • the 2OS proteasome is a cylindrical-shaped multicatalytic protease complex comprised of 28 subunits organized into four rings, and is the principal regulator of intracellular protein degradation in mammalian cells.
  • the 2OS proteasome exists principally as a subunit of the 26S proteasome, a multisubunit protein complex comprised of the 2OS core subunit capped at either one or both ends by the 19S regulatory complex, which serves to recognize ubiquitylated proteins and to convert them into a form capable of being degraded by the 2OS core complex.
  • the 2OS proteasome cleaves proteins via the coordinated catalytic activities of three distinct proteolytic sites having chymotryptic, tryptic, and post-glutamyl peptide hydrolytic-like activities.
  • An antineoplastic proteasome inhibitor inhibits the activity of the 26S proteasome via interaction with components of the 2OS core subunit that comprises the proteolytic sites, or via interaction with components of the 19S regulatory subunits that recognize proteins targeted for degradation and facilitate the unfolding and translocation of targeted proteins into the 2OS core subunit for proteolytic degradation.
  • proteasome inhibitors of the present invention are derived from effects on modulators of cell-cycle regulation, modulation of a balance between pro- and anti-apoptotic mechanisms, impacts on nuclear factor- ⁇ B (“NF- KB”) activity (e.g., by inhibiting proteasomal degradation of the NF-/cB inhibitor protein (“IKB”), and the unfolded protein response.
  • NF- KB nuclear factor- ⁇ B
  • the antineoplastic proteasome inhibitor selectively and reversibly inhibits the proteolytic site having chymotryptic-like activity, thereby inhibiting the degradation of proteins critically involved in regulation of cell proliferation and survival, ultimately leading to growth inhibition and apoptosis.
  • the antineoplastic proteasome inhibitor selectively and reversibly inhibits the proteolytic site having post-glutamyl peptide hydrolytic-like activity, hi another embodiment, the antineoplastic proteasome inhibitor selectively and reversibly inhibits the proteolytic site having trypsin-like activity.
  • the antineoplastic proteasome inhibitor irreversibly inhibits the proteolytic activity of the 2OS core subunit.
  • antineoplastic proteasome inhibitors are useful in the present invention, including for example, antineoplastic boronic ester and acid compounds, antineoplastic lactacystin analogs, antineoplastic peptide epoxides and peptide aziridines, antineoplastic peptide aldehydes, antineoplastic peptide vinyl sulfones, and antineoplastic cyclic tripeptides.
  • the antineoplastic proteasome inhibitor is selected from bortezomib, lactacystin, clasto-lactacystin /3-lactone, epoxomicin, eponemycin, carbobenzoxy-leucyl-leucyl-leucinal (MG- 132), carbobenzoxy-leucyl-leucyl-norvalinal (MG- 115), carbobenzoxy-isoleucyl-7-t-butyl-glutamyl-alanyl-leucinal (PSI), carbobenzoxy-leucyl- leucyl-leucine vinyl sulfone, and TMC-95A.
  • Antineoplastic boronic ester and acid compounds useful in accordance with the present invention include those compounds that reduce the cellular content and activity of NF- ⁇ B and reduce the rate of intracellular protein breakdown.
  • the antineoplastic boronic ester or acid compound of the present invention has the formula:
  • Rl R2 R3 (IV). [0062] In Formula (IV), P is R 4 -C(O)- or R 4 -S(O 2 )- and R 4 is selected from the group
  • R 1 is hydrogen or alkyl
  • R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, and -CH 2 -R 5 .
  • R 5 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or -Y-R 6 , where Y is a chalcogen and R 6 is alkyl.
  • Z 1 and Z are independently alkyl, hydroxy, heteroalkyl, aryloxy, or together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, the chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms.
  • antineoplastic boronic ester or acid compound is bortezomib.
  • Antineoplastic peptide epoxides and peptide aziridines useful in accordance with the present invention include those compounds that selectively inhibit the chymotrypsin-like activity of the 2OS proteasome, as compared to the trypsin-like and post-glutamyl peptide hydrolytic-like activities, those compounds that selectively inhibit the post-glutamyl peptide hydrolytic-like activity of the 2OS proteasome, as compared to the chymotrypsin-like and trypsin-like activites, and those compounds that selectively inhibit the trypsin-like activity of the 2OS proteasome, as compared to the chymotrypsin-like and post-glutamyl peptide hydrolytic-like activities.
  • the antineoplastic peptide epoxide or peptide aziridine of the present invention has
  • X is a heteroatom
  • R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 4 ) hydroxy substituted alkyl, (C 1 -C 6 ) heteroalkyl, aryl, or (C 1 -C 6 ) aryl substituted alkyl, any of which can be substituted with amide linkages, amines, carboxylic acids and salts thereof, carboxyl esters, thiols, or thioethers.
  • R 6 is a chain of amino acids, hydrogen, an acetyl group, or a protecting group.
  • the antineoplastic peptide epoxide or peptide aziridine is epoxomicin.
  • antineoplastic peptide epoxide or peptide aziridine of the present invention has the formula:
  • X is a heteroatom
  • R 1 is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) hydroxy substituted alkyl
  • R 2 and R 3 are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 4 ) hydroxy substituted alkyl, (Ci-C 6 ) heteroalkyl, aryl, or (Ci-C 6 ) aryl substituted alkyl, any of which can be substituted with amide linkages, amines, carboxylic acids and salts thereof, carboxyl esters, thiols, or thioethers, and R 4 is (C 1 -Ci 0 ) alkyl.
  • antineoplastic peptide aldehydes useful in accordance with the present invention include those compounds that reduce the rate of intracellular protein breakdown, including the rate of degradation of p53 protein.
  • the antineoplastic peptide aldehyde of the present invention has the formula:
  • R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and arylalkyl, and a is 0 or 1.
  • R 5 is selected from -C(O)-R' or an amino-group protecting moiety, and R' is alkyl, heteroalkyl, aryl, or arylalkyl.
  • the antineoplastic peptide aldehyde is selected from carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG- 132), carbobenzoxy-L-leucyl-L- leucyl-L-norvalinal (MG-115), or carbobenzoxy-isoleucyl- ⁇ -t-butyl-glutamyl-alanyl-leucinal (PSI).
  • Antineoplastic lactacystin analogs useful in accordance with the present invention include those compounds that inhibit cell cycle progression through inhibition of the 2OS proteasome.
  • the antineoplastic lactacystin analog of the present invention has the formula:
  • R 1 is selected from alkyl, cycloalkyl, heteroalkyl, hydroxy, aryl, arylalkyl, or amido.
  • R 2 and R 3 are independently selected from alkyl, cycloalkyl, heteroalkyl, aryl, or arylalkyl.
  • the antineoplastic lactacystin analog is lactacystin.
  • antineoplastic lactacystin analog of the present invention has the formula:
  • R 1 and R 2 are as defined hereinbefore with reference to Formula (VIII).
  • the antineoplastic lactacystin analog of the present invention is clasto-lactacystin 0-lactone.
  • Antineoplastic peptide vinyl sulfones useful in accordance with the present invention include those compounds that inhibit the chymotrypsin-like, the trypsin-like, and the post-glutamyl peptide hydrolytic-like activity of the 2OS proteasome through covalent modification of the active site threonine of the catalytic ⁇ -subunits of the proteasome.
  • the antineoplastic peptide vinyl sulfone of the present invention has the formula:
  • R 1 is selected from (Ci-C 6 ) alkyl.
  • R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and arylalkyl, and a is 0 or 1.
  • R 6 is selected from -C(O)-R' or an amino-group protecting moiety, and R' is alkyl, heteroalkyl, aryl, or arylalkyl.
  • the antineoplastic peptide vinyl sulfone is carbobenzoxy-leucyl-leucyl-leucine vinyl sulfone.
  • Antineoplastic cyclic tripeptides useful in accordance with the present invention include those compounds that inhibit the chymotrypsin-like, the trypsin-like, and the post- glutamyl peptide hydrolytic-like activity of the 2OS proteasome, including those compounds that reversibly inhibit the 2OS proteasome.
  • the antineoplastic cyclic tripeptide of the present invention has the formula:
  • R 2A and R 2B are independently selected from hydrogen or hydroxy.
  • R 3 is hydrogen, alkyl, or heteroalkyl.
  • R 4A and R 4B are independently selected from hydrogen or (C 1 -C 6 ) alkyl, and R 5 is (C 1 -C 6 ) alkyl.
  • Embodiments of combinations of an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor were investigated for potential therapeutic synergy.
  • the drug concentrations and ratios used in the combination studies were determined from the IC 5 o values of single-drug experiments in each of various cell lines, and the concentration ranges used for each combination study were developed by making incremental concentration changes above and below the IC 50 value for each drug as a single agent.
  • each second antineoplastic agent e.g., bortezomib
  • IC 50 of each second antineoplastic agent was compared to the ICs 0 value for imexon and a fixed constant ratio was established for use in the subsequent combination drug exposure experiments.
  • cytotoxic effects of embodiments of combinations of the present invention were determined using standard 3-(4,5-dimethylthiazole)-2,5-diphenyl tetrazolium bromide (MTT) or sulphorhodamine B (SRB) analyses.
  • MTT 3-(4,5-dimethylthiazole)-2,5-diphenyl tetrazolium bromide
  • SRB sulphorhodamine B
  • Human malignant melanoma A375 cells and human myeloma RPMI 8226 cells were obtained from the American Type Culture Collection (Manassas, VA). Both cell lines were cultured in RPMI 1640 media (Gibco-BRL Products, Grand Island, NY) supplemented with 10% (v/v) heat-inactivated bovine calf serum (Hyclone Laboratories, Logan, UT), 2 mM L-glutamine, penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml) in a humidified incubator containing 5% CO2 at 37° C.
  • RPMI 1640 media Gibco-BRL Products, Grand Island, NY
  • bovine calf serum Hyclone Laboratories, Logan, UT
  • penicillin 100 U/ml
  • streptomycin 100 ⁇ g/ml
  • Bortezomib was purchased from Millenium Pharmaceuticals (Cambridge, MA), epoxomicin and clasto-lactacystin ⁇ -lactone were purchased from BioMol International (Plymouth Meeting, PA), and imexon was obtained from the National Cancer Institute.
  • Table 1 illustrates the results of the combination experiments conducted using an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor. Neither the illustrated results, nor the specific combination embodiments selected, are intended to limit the scope of the present invention.
  • Proteasome Inhibitor A375 Melanoma Cell Line RPMI 8226 Myeloma Cell Line Bortezomib Additive Synergistic
  • synergy was identified in one or more cell lines for each of the combinations evaluated.
  • the combination of imexon and bortezomib had a C.I. ranging from 0.59-1.27 (additive) in the A375 cell line, and a C.I. ranging from 0.60-0.86 (synergistic) in the RPMI 8226 cell line.
  • the combination of imexon and epoxomicin had a C.I. ranging from 0.58-0.90 (synergistic) in the A375 cell line, and C.I. ranging from 0.46-1.17 (additive) in the RPMI 8226 cell line.
  • 8-lactone had a C.I. ranging from 0.86-0.98 (synergistic) in the A375 cell line, and a C.I. ranging from 0.60-0.94 (synergistic) in the RPMI 8226 cell line.
  • the present invention provides assays to determine whether a combination of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent has a synergistic therapeutic cytotoxic effect.
  • a "synergistic therapeutic cytotoxic effect" means that a given combination of at least 2 compounds exhibits synergy when tested in a cytotoxic assay.
  • synergy is assessed using the median-effect principle (Chou, et al., Adv Enzyme Regul 22:27-55 (1984)). This method is based on Michaelis- Menton kinetics and reduces combination effects to a numeric indicator, the combination index (CL). Where the combination index is less than 1, synergism is indicated. Where the combination index is equal to 1, summation is indicated. Where the combination index is greater than 1 , antagonism is indicated.
  • C.I. values One skilled in the art will recognize that it is possible to see mixed effects over a range of C.I. values. Therefore, only combinations that are consistent over at least the majority of the drug concentration range are classified as synergistic, additive, or antagonistic.
  • the combination index of an antineoplastic thiol- binding mitochondrial oxidant and a second antineoplastic agent is less than 1.0. In another exemplary embodiment, the combination index of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent is at least less than 0.9. In another exemplary embodiment, the combination index of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent is at least less than 0.8. In another exemplary embodiment, the combination index of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent is at least less than 0.7. In another exemplary embodiment, the combination index of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent is at least less than 0.6.
  • a number of biological assays are available to evaluate and to optimize the choice of specific combinations of compounds for optimal antitumor activity. These assays can be roughly split into two groups: Those involving in vitro exposure of agents to tumor cells; and those involving in vivo antitumor assays in rodent models and rarely, in larger animals. Both in vitro assays using tumor cells and in vivo assays in animal models are discussed below, and are equally applicable to determining whether a thiol-binding mitochondrial oxidant, or a proteasome inhibitor exhibits antineoplastic properties.
  • Cytotoxic assays in vitro for a combination of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent generally involve the use of established tumor cell lines both of animal and, especially, of human origin. These cell lines can be obtained from commercial sources such as the American Type Tissue Culture Laboratory in Bethesda, Maryland, and from tumor banks at research institutions. Exposures to combinations of the present invention may be carried out under simulated physiological conditions of temperature, oxygen and nutrient availability in the laboratory.
  • the endpoints for these in vitro assays can involve: 1) colony formation; 2) a simple quantitation of cell division over time; 3) the uptake of so called "vital" dyes, which are excluded from cells with an intact cytoplasmic membrane; and 4) the incorporation of radiolabeled nutrients into a proliferating (viable) cell.
  • Colony forming assays have been used both with established cell lines, as well as fresh tumor biopsies surgically removed from patients with cancer. In this type of assay, cells are typically grown in petri dishes on soft agar, and the number of colonies or groups of cells (>60 .mu. in size) are counted either visually, or with an automated image analysis system.
  • Coulter.RTM. counter. Control (untreated) cell growth rates are then compared to the treated (with a combination of antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent) cell growth rates.
  • Vital dye staining is another one of the older hallmarks of antitumor assays. In this type of approach, cells, either untreated or treated with a cancer drug, are subsequently exposed to a dye such as methylene blue, which is normally excluded from intact (viable) cells. The number of cells taking up the dye (dead or dying) are the numerator with a denominator being the number of cells which exclude the dye.
  • Anticancer combinations are typically then injected at some later time point(s), either by intraperitoneally or intravenously, or administered orally, and tumor growth rates and/or survival are determined, compared to untreated controls or controls having only an antineoplastic thiol-binding mitochondrial oxidant or a second antineoplastic agent.
  • growth rates are typically measured for tumors injected growing in the front flank of the animal, wherein perpendicular diameters of tumor width are translated into an estimate of total tumor mass or volume.
  • significant findings generally involve a >25% increase in the time to reach the predetermined mass in the treated animals compared to the controls, hi other embodiments, significant findings involve a >42% increase in the time to reach the predetermined mass in the treated animals compared to the controls.
  • the significant findings are termed tumor growth inhibition. For non-localized tumors such as leukemia, survival can be used as an endpoint and a comparison is made between the treated animals and the untreated or solvent treated controls. In general, a significant increase in life span for a positive new agent is again >20-42% longer life span due to the treatment. Early deaths, those occurring before any of the untreated controls, generally indicate toxicity for a new compound.
  • the anticancer combinations are generally tested at doses very near the lethal dose and 10% (LD 1O ) and/or at the determined maximally-tolerated dose, that dose which produces significant toxicity, but no lethality in the same strain of animals and using the same route of administration and schedule of dosing. Similar studies can also be performed in rat tumor models, although, because of the larger weight and difficulty handling these animals, they are less preferred than the murine models.
  • SCID mice A number of human tumors are known to successfully "take” in the nude mouse model, even though these animals are more susceptible to intercurrent infections due to the underlying immunologic deficiency.
  • An alternative mouse model for this work involves mice with a severe combined immunodeficiency disease (SCID) wherein there is a defect in maturation of lymphocytes. Because of this, SCID mice do not produce functional B- and T-lymphocytes. However, these animals do have normal cytotoxic T-killer cell activity. Nonetheless, SCID mice will "take” a large number of human tumors. Animals with the SCID phenotype are screened for "leakiness" by measuring serum immunoglobulin production which should be minimal to undetectable if the SCID phenotype is maintained.
  • SCID mice Tumor measurements and drug dosing are generally performed as above.
  • the use of SCID mice has in many cases displaced the nude mouse since SCID mice seem to have a greater ability to take a larger number of human tumors and are more robust in terms of lack of sensitivity to intercurrent infections.
  • positive compounds in the SCID mouse model are those that inhibit tumor growth rate by >20-42% compared to the untreated control.
  • Testing for drug resistance can involve any of the in vitro and in vivo models, although the in vitro models are better characterized.
  • a cell subline is developed for resistance to a particular agent generally by serial exposure to increasing concentrations of the anticancer combination either in vitro or rarely in vivo.
  • the cell line is further studied for mechanisms of resistance such as the expression of multidrug resistance membrane pumps such as p-glycoprotein or others.
  • These resistant cell lines can then be tested for cross-resistance with classic anticancer agents to develop a response pattern for a particular cell line.
  • All of these test systems are generally combined in a serial order, moving from in vitro to in vivo, to characterize the antitumor activity of an anticancer combination.
  • experiments are then planned in rodent models to evaluate whether or not the combinations that have shown activity in vitro will be tolerated and active in animals.
  • the initial experiments in animals generally involve toxicity testing to determine a tolerable dose schedule and then using that dose schedule, to evaluate antitumor efficacy as described above.
  • Active combinations from these two types of assays may then be tested in human tumors growing in SCID or nude mice and, if activity is confirmed, these combinations then become candidates for potential clinical drug development.
  • antineoplastic thiol-binding mitochondrial oxidants of the present invention are those compounds that inhibit or prevent the growth of cancer, are capable of binding thiol moieties, and promote oxidative stress and disruption of cellular mitochondrial membrane potential, hi some embodiments, the antineoplastic thiol-binding mitochondrial oxidant inhibits or reduces activity of a ribonucleotide reductase inhibitor. Cytotoxic assays useful for determining whether a compound is antineoplastic are discussed above (see Assays for Testing the Anticancer Synergistic Activity of a Combination of an Antineoplastic Thiol-binding Mitochondrial Oxidant and a Second Antineoplastic Agent). Assays for measuring other characteristics are described below.
  • the ability of a test compound to bind to a thiol-containing molecule may be assessed by mixing the test compound in aqueous solution with a thiol-containing molecule, such as cysteine or glutathione. The solution is incubated for sufficient time to allow binding of the thiol moiety to the test compound to form a reaction product. After incubating the mixture for a sufficient time, any appropriate separation method (e.g., thin layer chromatography (TLC)) may be performed on the solution to isolate the reaction product. After isolation, the reaction product is optionally further purified (e.g., by filtration) and detected using any appropriate technique, such as nuclear magnetic resonance or mass spectroscopy.
  • TLC thin layer chromatography
  • the presence of oxidative stress may be assessed using an antibody capable of binding to oxidized nucleotides, such as the well characterized monoclonal antibody 8- OHdG.
  • the appropriate cell line such as myeloma cells, may be treated with a test compound at various time points. The cells may then be fixed with formaldehyde and subsequently permeabilized with methanol. The cell can then be immunostained with the appropriate anti-oxidized nucleotide antibody and visualized using any appropriate detection technique, such as a secondary antibody system (e.g., biotinylated secondary antibody and subsequent addition of Cy5-conjugated streptavidin). Nuclear localization may then be accomplished using an appropriate nuclear stain, such as YOYO-I. RTM. stain (Molecular Probes). Laser confocal microscopy may then be used to visualize oxidative damage within the mitochondrial cellular compartment.
  • MMP mitochondrial membrane potential
  • Ribonucleotide reductase activity may be measured by first contacting a cell culture with the appropriate test compound. The cells are then harvested and the cell lysate purified by an appropriate technique to separate deoxycytidine (the specific product of RNR activity) and cytidine after phosphorylation (such as Aff ⁇ gel 601 column or a high- resolution HPLC C- 18 column). The amount of deoxycytine product is measured and compared to the amount of product produced by the cell in the absence of added test compound, thereby determining the ability of the test compound to inhibit or decrease RNR activity.
  • RNR Ribonucleotide reductase activity
  • deoxyribonucleotides are detected via coupling to the DNA polymerase reaction with enhanced detection using RNAse to degrade endogenous RNA.
  • a pharmaceutical composition of the present invention can be micronized or powdered so that it is more easily dispersed and solubilized by the body. Processes for grinding or pulverizing drugs are well known in the art, for example, by using a hammer mill or similar milling device.
  • Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligram to about 5000 milligrams of active ingredient per unit, hi these pharmaceutical compositions, the active ingredient may be present in an amount of about 0.5 to about 95% by weight based on the total weight of the composition.
  • Another convention for denoting the dosage form is in mg per meter squared (mg/m 2 ) of body surface area (BSA).
  • BSA body surface area
  • an adult will have approximately 1.75 m 2 of BSA.
  • the dosage may be administered in one or more doses several times per day or per week.
  • Multiple dosage units may be required to achieve a therapeutically effective amount.
  • the dosage form is 1000 mg, and the patient weighs 40 kg, one tablet or capsule will provide a dose of 25 mg per kg for that patient. It will provide a dose of only 12.5 mg/kg for an 80 kg patient.
  • a dosage of as little as about 1 milligram (mg) per kilogram (kg) of body weight and up to about 10,000 mg per kg of body weight is suitable as a therapeutically effective dose.
  • a dosage of from about 5 mg/kg to about 2500 mg/kg of body weight is used.
  • Other preferred doses range between 25 mg/kg to about 1000 mg/kg of body weight.
  • a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight to about 400 mg per kg of body weight is also suitable for treating some cancers.
  • the most preferred rates of administration can range from about 1 to about 1000 mg/kg/minute during a constant rate infusion.
  • a pharmaceutical composition of the present invention can be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • An antineoplastic thiol- binding mitochondrial oxidant is generally given in one or more doses on a daily basis or from one to five times per week.
  • a pharmaceutical composition of the present invention is administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents.
  • an antineoplastic thiol-binding mitochondrial oxidant and second antineoplastic agent in treating cancers can vary according to patient response and physiology, type and severity of side effects, the disease being treated, the preferred dosing regimen, patient prognosis or other such factors.
  • the ratio of an antineoplastic thiol-binding mitochondrial oxidant to the second antineoplastic agent can be varied as needed according to the desired therapeutic effect, the observed side-effects of the combination, or other such considerations known to those of ordinary skill in the medical arts.
  • the ratio of an antineoplastic thiol-binding mitochondrial oxidant to a second antineoplastic agent can range from about 0.5%:99.5% to about 99.5%:0.5% on a weight basis, hi an exemplary embodiment, the ratio can range from about 20%: 80% to about 80%: 20%.
  • the ratio can range from about 40%:60% to about 60%:40%.
  • the ratio can range from about 45%:55% to about 55%:45%. In another exemplary embodiment, the ratio can be about 50%:50%.
  • an antineoplastic thiol-binding mitochondrial oxidant is administered before or after a second antineoplastic agent
  • the respective doses and the dosing regimen of an antineoplastic thiol-binding mitochondrial oxidant and the second antineoplastic agent can vary.
  • the adjunct or combination therapy can be sequential, that is, treatment with the antineoplastic thiol-binding mitochondrial oxidant is followed by treatment with the second antineoplastic agent (or vice versa), or it can be concomitant treatment wherein the antineoplastic thiol-binding mitochondrial oxidant and the second antineoplastic agent are administered substantially at the same time.
  • the administration of the second chemotherapeutic agent can be accomplished within any reasonable time after the administration of the first chemotherapeutic agent.
  • the treatment with both agents at the same time can be in the same daily dose or in separate doses.
  • a full dosing regimen of an antineoplastic thiol-binding mitochondrial oxidant can be administered either before or after a full dosing regimen of the second antineoplastic agent, or alternating doses of an antineoplastic thiol-binding mitochondrial oxidant and the second antineoplastic agent can be administered.
  • an antineoplastic thiol-binding mitochondrial oxidant can be administered concomitantly with the second antineoplastic agent.
  • the identity of the second antineoplastic agent, the pharmaceutical carrier and the amount of an antineoplastic thiol-binding mitochondrial oxidant administered can vary widely depending on the species and body weight of mammal and the type of cancer or viral infections being treated.
  • the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics of a specific second antineoplastic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
  • An antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent can be administered together in a single dosage form or separately in two or more different dosage forms. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
  • a dosage unit can comprise a single compound or mixtures of an antineoplastic thiol-binding mitochondrial oxidant with one or more second antineoplastic agents.
  • An antineoplastic thiol-binding mitochondrial oxidant can be administered in oral dosage forms such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • An antineoplastic thiol-binding mitochondrial oxidant or second antineoplastic agent can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • An antineoplastic thiol-binding mitochondrial oxidant or second antineoplastic agent is typically administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
  • compositions can be administered alone or can be mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • Tablets can contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • compositions can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • compositions can also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • Suitable soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacry- lamide-phenol, polyhydroxyethylasparta- midephenol, and polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • an antineoplastic thiol-binding mitochondrial oxidant can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms.
  • Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • liquid dosage form For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose
  • sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • compositions can also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • suitable intranasal vehicles or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • kits useful, for example, for the treatment of cancer which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of an antineoplastic thiol-binding mitochondrial oxidant and a second antineoplastic agent, respectively.
  • Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Printed instructions either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
  • the method of treatment can be any suitable method that is effective in the treatment of the particular cancer or tumor type being treated.
  • Treatment can be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer.
  • the method of applying an effective amount also varies depending on the disorder or disease being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of an antineoplastic thiol-binding mitochondrial oxidant, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
  • Tumor load is assessed prior to therapy by means of objective scans of the tumor such as with x-ray radiographs, computerized tomography (CAT scans), nuclear magnetic resonance (NMR) scans or direct physical palpation of the tumor mass.
  • the tumor may secrete a marker substance such as alphafetoprotein from colon cancer, CAl 25 antigen from ovarian cancer, or serum myeloma "M" protein from multiple myeloma. The levels of these secreted products then allow for an estimate of tumor burden to be calculated.
  • These direct and indirect measures of the tumor load are done pretherapy, and are then repeated at intervals following the administration of the drug in order to gauge whether or not an objective response has been obtained.
  • An objective response in cancer therapy generally indicates >50% shrinkage of the measurable tumor disease (a partial response), or complete disappearance of all measurable disease (a complete response). Typically these responses must be maintained for a certain time period, usually one month, to be classified as a true partial or complete response. In addition, there may be stabilization of the rapid growth of a tumor or there may be tumor shrinkage that is ⁇ 50%, termed a minor response or stable disease. In general, increased survival is associated with obtaining a complete response to therapy and in some cases, a partial response, if maintained for prolonged periods can also contribute to enhanced survival in the patient. Patients receiving chemotherapy are also typically "staged" as to the extent of their disease before beginning chemotherapy, and are then restaged following chemotherapy to see if this disease extent has changed.
  • the tumor may shrink sufficiently, and if no metastases are present, to make surgical excision possible after chemotherapy treatment where it was not possible beforehand due to the widespread disease.
  • the chemotherapy treatment with the novel pharmaceutical compositions is being used as an adjuvant to potentially curative surgery.
  • patients may have individual lesions in the spine or elsewhere that produce symptomatic problems such as pain and these may need to have local radiotherapy applied. This may be done in addition to the continued use of the systemic pharmaceutical compositions of the present invention.
  • Patients are assessed for toxicity with each course of chemotherapy, typically looking at effects on liver function enzymes and renal function enzymes such as creatinine clearance or BUN as well as effects on the bone marrow, typically a suppression of granulocytes important for fighting infection and/or a suppression of platelets important for hemostasis or stopping blood flow.
  • liver function enzymes and renal function enzymes such as creatinine clearance or BUN
  • effects on the bone marrow typically a suppression of granulocytes important for fighting infection and/or a suppression of platelets important for hemostasis or stopping blood flow.
  • myelosuppressive drugs the nadir in these normal blood counts is reached between 1-3 weeks after therapy and recovery then ensues over the next 1-2 weeks. Based on the recovery of normal white blood counts, treatments may then be resumed.
  • Treatment schedules or dosing regimens for the administration of compounds or pharmaceutical compositions in accordance with the present invention conventionally comprise cycles of treatment wherein a specified dose of each composition of the synergistic combination is administered to a patient at defined intervals over the period of a cycle, and then repeated in each subsequent cycle.
  • the period of a cycle may be defined in any suitable manner, and may comprise, for example, a twenty-one day cycle, a twenty-eight day cycle, or the like.
  • the specified dose of a compound in accordance with the present invention can be administered to the patient at defined intervals, such as for example, for five consecutive days every other week (e.g., days 1-5 and 15-19 of a 28-day cycle), for five consecutive days every three weeks (e.g., days 1-5 of a 21-day cycle), once per week (e.g., days 1, 8 and 15 of a 21 -day cycle), or the like.
  • bone marrow biopsies can be used to quantitate the number of abnormal tumor plasma cells present in the specimen.
  • higher dose therapy is typically used to affect responses in the bone marrow and/or lymphatic compartments.
  • the projected clinical uses for the novel pharmaceutical formulations are as treatments for any cancers sensitive to the combination therapy, and in particular hematological malignancies.
  • Combinations comprising an antineoplastic thiol-binding mitochondrial oxidant and an antineoplastic proteasome inhibitor may be useful in the treatment of lung cancer, breast cancer, malignant melanoma, colon cancer, pancreatic cancer, prostate cancer, ovarian epithelial cell cancer, multiple myeloma, and leukemias and lymphomas.

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Abstract

L'invention concerne des compositions et des méthodes utiles dans le traitement du cancer. Des modes de réalisation de la présente invention incluent des compositions et des méthodes faisant appel à une combinaison synergique d'un oxydant mitochondrial antinéoplasique se liant au thiol et d'un inhibiteur du protéasome antinéoplasique.
PCT/US2007/078119 2006-09-13 2007-09-11 Combinaisons synergiques d'oxydants mitochondriaux antinéoplasiques se liant au thiol et d'inhibiteurs du protéasome antinéoplasiques pour le traitement du cancer WO2008033807A2 (fr)

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US9205124B2 (en) 2005-11-09 2015-12-08 Onyx Therapeutics, Inc. Compounds for enzyme inhibition
US9205125B2 (en) 2005-11-09 2015-12-08 Onyx Therapeutics, Inc. Compounds for enzyme inhibition
US9205126B2 (en) 2005-11-09 2015-12-08 Onyx Therapeutics, Inc. Compounds for enzyme inhibition
US10150794B2 (en) 2005-11-09 2018-12-11 Onyx Therapeutics, Inc. Compounds for enzyme inhibition
US9657058B2 (en) 2006-06-19 2017-05-23 Onyx Therapeutics, Inc. Compounds for enzyme inhibition
US8921583B2 (en) 2007-10-04 2014-12-30 Onyx Therapeutics, Inc. Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides
US8921324B2 (en) 2007-10-04 2014-12-30 Onyx Therapeutics, Inc. Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides
USRE47954E1 (en) 2008-10-21 2020-04-21 Onyx Therapeutics, Inc. Combination therapy with peptide epoxyketones
EP2349313A4 (fr) * 2008-10-21 2012-08-29 Onyx Therapeutics Inc Thérapie de combinaison avec des peptides époxycétones
US10596222B2 (en) 2008-10-21 2020-03-24 Onyx Therapeutics, Inc. Combination therapy with peptide epoxyketones
EP2349313A1 (fr) * 2008-10-21 2011-08-03 Onyx Therapeutics, Inc. Thérapie de combinaison avec des peptides époxycétones
EA024364B1 (ru) * 2008-10-21 2016-09-30 Оникс Терапьютикс, Инк. Способ лечения множественной миеломы
US9511109B2 (en) 2008-10-21 2016-12-06 Onyx Therapeutics, Inc. Combination therapy with peptide epoxyketones
JP2012506445A (ja) * 2008-10-21 2012-03-15 オニキス セラピューティクス， インク． ペプチドエポキシケトンを用いた併用療法
US9051353B2 (en) 2009-03-20 2015-06-09 Onyx Therapeutics, Inc. Crystalline tripeptide epoxy ketone protease inhibitors
US9403868B2 (en) 2009-03-20 2016-08-02 Onyx Therapeutics, Inc. Crystalline tripeptide epoxy ketone protease inhibitors
US8853147B2 (en) 2009-11-13 2014-10-07 Onyx Therapeutics, Inc. Use of peptide epoxyketones for metastasis suppression
US9359398B2 (en) 2010-03-01 2016-06-07 Onyx Therapeutics, Inc. Compounds for immunoproteasome inhibition
US9315542B2 (en) 2012-07-09 2016-04-19 Onyx Therapeutics, Inc. Prodrugs of peptide epoxy ketone protease inhibitors
US9878047B2 (en) 2012-07-09 2018-01-30 Onyx Therapeutics, Inc. Prodrugs of peptide epoxy ketone protease inhibitors
US9309283B2 (en) 2012-07-09 2016-04-12 Onyx Therapeutics, Inc. Prodrugs of peptide epoxy ketone protease inhibitors
US10682419B2 (en) 2012-07-09 2020-06-16 Onyx Therapeutics, Inc. Prodrugs of peptide epoxy ketone protease inhibitors
CN104974221A (zh) * 2014-04-03 2015-10-14 中国医学科学院药物研究所 二肽及三肽类蛋白酶体抑制剂及其制法和药物用途
CN104974221B (zh) * 2014-04-03 2020-10-23 中国医学科学院药物研究所 二肽及三肽类蛋白酶体抑制剂及其制法和药物用途

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