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WO2002036574A1 - Derives de geldanamycine utiles dans le traitement du cancer - Google Patents

Derives de geldanamycine utiles dans le traitement du cancer Download PDF

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Publication number
WO2002036574A1
WO2002036574A1 PCT/US2001/044172 US0144172W WO0236574A1 WO 2002036574 A1 WO2002036574 A1 WO 2002036574A1 US 0144172 W US0144172 W US 0144172W WO 0236574 A1 WO0236574 A1 WO 0236574A1
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Prior art keywords
compound
hsp90
grp94
cell
hif
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PCT/US2001/044172
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English (en)
Inventor
Kenneth M. Snader
Leonard M. Neckers
B. Roa Vishnuvajjala
Edward A. Sausville
Wanping Xu
Meredith F. Rosser
Christopher Nicchitta
Jennifer A. Isaacs
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The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Application filed by The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services filed Critical The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services
Priority to AU2002217866A priority Critical patent/AU2002217866A1/en
Publication of WO2002036574A1 publication Critical patent/WO2002036574A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains to geldanamycin derivatives and methods of using the geldanamycin derivatives, for example, to treat cancer.
  • ErbB2 gene product and the HIF-l ⁇ protein are believed to play important roles in the malignancy and growth of tumor cells.
  • the HIF-l ⁇ protein is a transcription factor that is recognized as a pro- survival factor in many types of cancer, and some tumor cells rely on HIF-l ⁇ to stimulate many cellular processes, such as the transcriptional activation of NEGF, which is used to produce new blood vessel growth in tumor tissues.
  • Geldanamycin also is a specific inhibitor of certain chaperone proteins including the heat shock protein-90 (Hsp90) as well as the glucose regulated protein-94 (Grp94), which is localized to the endoplasmic reticulum. It is believed that geldanamycin acts on the ErbB2 protein through its inhibition of the Hsp90 chaperone protein, which is thought to be necessary to the function of the ErbB2 protein. Hsp90 also has been shown to be linked to tumor cell proliferation (see L. Whitesell et al., Inhibition of Heat Shock Protein HSP-90-pp60v-src Heteroprotein Complex Formation by Benzoquinone Ansamycins: Essential Role for Stress Proteins in Oncogenic Transformation, 91 Proc.
  • R 3 is a C ⁇ -C 8 aminoalkyl or a C ⁇ -C 8 iminoalkyl;
  • R 4 is hydrogen, a methoxy, a C ⁇ -C 8 alkylamino, a C ⁇ -C 8 dialkylamino, a C ⁇ -C 8 N,N'- dialkylaminoalkylamino, or an allylamino;
  • R 5 is hydrogen or a group of the formula (II)
  • each of R 6 , R 7 , and R 8 is independently selected from the group consisting of hydrogen, a halo, an azido, a nitro, a C ⁇ -C 8 alkyl, a C ⁇ -C 8 alkoxy, an aryl, a cyano, and an NR 10 R ⁇ R 12 , wherein each of R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and a C 1 -C 3 alkyl; and salts thereof and prodrugs thereof.
  • the present invention also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • a method of selectively inhibiting Hsp90 without substantially inhibiting Grp94 in a cell comprises administering to a cell comprising Hsp90 and Grp94 an above-described compound in an amount sufficient to inhibit Hsp90 without substantially inhibiting Grp94, whereupon Hsp90 is selectively inhibited.
  • the present invention additionally provides a method of inhibiting HIF- 1 ⁇ in a cell.
  • the method comprises administering to a cell comprising HIF-l ⁇ an above- described compound in an amount sufficient to inhibit HIF-l ⁇ .
  • Still further provided is a method of treating or preventing cancer in a host.
  • the method comprises administering an above-described compound to a host in an amount sufficient to treat or prevent cancer in the host, whereupon the cancer in the host is treated or prevented.
  • the present invention provides a compound of formula (I),
  • R 3 is a C ⁇ -C 8 aminoalkyl or a C ⁇ -C 8 iminoalkyl, either of which can be substituted with one or more C ⁇ -C 4 alkyl groups, which can be the same or different.
  • R 4 is hydrogen, a methoxy, a C ⁇ -C 8 alkylamino, a Ct-C 8 dialkylamino, a C ⁇ -C 8 N,N'-dialkylaminoalkylamino, or an allylamino.
  • R 4 When R 4 is a methoxy, a C ⁇ -C 8 alkylamino, a C ⁇ -C 8 dialkylamino, a C ⁇ -C 8 N,N'-dialkylaminoalkylamino, or an allylamino, R 4 can be substituted with one or more substituents, which can be the same or different, selected from the group consisting of a C ⁇ -C 4 alkyl, a - aryl, a halo, a cyano, a nitro, an azido, an amido, and an amino.
  • R 5 is hydrogen or a group of the formula (II)
  • each of R 6 , R 7 , and R 8 is independently selected from the group consisting of hydrogen, a halo, an azido, a nitro, a C ⁇ -C 8 alkyl, a -Cs alkoxy, an aryl, a cyano, and an NR 10 R n R 12 , wherein each of R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and a Q-C 3 alkyl; and salts thereof and prodrugs thereof.
  • Positions indicated by the numbers 1-21 on the benzoquinone ansamycin ring in formula (I) represent carbon atoms.
  • particularly preferred compounds of the present invention include, geldanamycinglycinate, 17-demethoxy-17-allylamino geldanamycin- 11-aminoacetate, 17- demethoxy-17-allylamino geldanamycin- 1 l-[3-(dimethylamino)-propionate], 11-(4- aminobutyrate)-geldanamycin, and 17-demethoxy-17-allylamino geldanamycin-l l-[4- (dimethylamino)-butyrate], and, especially, salts (e.g., hydrochloride salts) thereof.
  • salts e.g., hydrochloride salts
  • Compounds of the present invention can be in the form of a salt, which is preferably a pharmaceutically acceptable salt.
  • suitable pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids, for example /?-toluenesulphonic acid.
  • prodrug is meant a compound of the present invention, wherein the R 3 , R 4 and/or R 5 groups can be cleaved-off by normal metabolic processes in vivo, thereby transforming the prodrug back into the parent geldanamycin compound. It will be understood that prodrugs are typically used when the active drug may be too toxic to administer systemically, the active drug is absorbed poorly by Ihe digestive tract, or the body breaks down the active drug before it reaches its target.
  • the compounds of the present invention have improved water- solubility as compared to Geldanamycin and/or have the ability to form salts (e.g. , acid salts) having improved water solubility as compared to geldanamycin, while retaining in vitro or in vivo anticancer or antitumor activity.
  • preferred compounds of the present invention have water-solubilities of at least about 0.5 mg/ml, preferably at least about 1 mg/ml (e.g., 1.5 mg/ml), more preferably at least about 2 mg/ml (e.g., at least about 2.5 mg/ml).
  • the compounds of the present invention have water- solubilities of at least about 3 mg/ml (e.g., at least about 3.5 mg/ml) or even at least about 4 mg/ml (e.g., at least about 4.5 mg/ml) or even greater water-solubilities (e.g., at least about 5 mg/ml).
  • Water-solubilities can be determined using standard techniques known in the art. While the compounds of the present invention, preferably, have improved water- solubility, techniques known in the art can be used in conjunction with the present invention to further improve the water-solubility of these compounds. For example, the pH of a formulation comprising the compound can be adjusted to optimize the water- solubility of the compound.
  • additives can be incorporated into a formulation comprising a compound of the present invention.
  • Useful additives include cosol vents (e.g., polyethylene glycol), surface active agents, complexing agents, emulsifying agents, amphiphilic compounds, liposomes, and micro- and nanoparticles, which may improve the solubility of a compound of the present invention.
  • Compounds of the present invention preferably have a strong binding affinity for Hsp90.
  • GA is known to have a strong affinity for Hsp90 and effectively inhibits the protein's function.
  • Preferred compounds of the present invention have a binding affinity for Hsp90 that is at least about 1/10 or more, preferably at least about l/5 th or more, of the binding affinity exhibited by GA for Hsp90.
  • the most preferred compositions have a binding affinity for Hsp90 that is about equal to, or even greater than, that of GA.
  • the compounds of the present invention preferably exhibit a binding affinity for Grp94 that is several-fold less than that exhibited by GA.
  • GA has a binding affinity for Grp94 that is about equal to its binding affinity for Hsp90.
  • Preferred compounds of the present invention exhibit a binding affinity for Grp94 that is about 1/20* or less, preferably about 1/40* or less, more preferably about l/60 th or less, or even about 1/80* or less, of the binding affinity for Grp94 exhibited by GA.
  • Preferred compounds of the present invention have a binding affinity for Hsp90 that is substantially greater than their binding affinity for Grp94.
  • the preferred compounds of the present invention have a binding affinity for Hsp90 that is at least 10-times greater, more preferably at least 40-times greater, even more preferably at least 80-times greater, than the binding affinity of the compound for Grp94.
  • Binding affinities and relative binding affinities can be measured by any suitable method known in the art including by copy of illustration, through the use of competitive binding assays and comparison of the concentration at which test compounds (e.g., GA or a compound of the present invention) binds to a given percentage of the target protein (e.g., Hsp90 or Grp94) in the presence of an inhibitor (e.g., another small molecule known to share, with the test compound, the same binding site on the target protein) and the like.
  • a preferred method of determining the relative binding affinities is by comparing the concentration of the test compound at which 50% of the target protein is bound (otherwise know as the IC5 0 concentration level) in a competitive binding assay.
  • the compounds of the present invention preferably, inhibit HIF-l ⁇ .
  • Preferred compounds of the present invention inhibit HIF-l ⁇ to a degree that is at least about 10% or more, preferably at least about 25% or more, such as at least about 50% or more, or even about 75% or more (e.g, approximately equal to or greater than) of the level of inhibition of HIF- l ⁇ exhibited by GA.
  • the level of inhibition can be determined, for example, by measuring the level of HIF-l ⁇ activity in a cell in the presence of a compound of the present invention or in the presence of GA as compared to the level of activity in the absence of such compounds.
  • the present invention further provides a pharmaceutical composition or formulation comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition or formulation preferably comprises a compound of the present invention in an amount sufficient to inhibit Hsp90 without substantially inhibiting Grp94 when administered to a host having cells comprising Hsp90 and Grp94.
  • the amount is sufficient to reduce substantially or eliminate the expression of ErbB2 proteins when administered to a host having cells that express the ErbB2 protein in the absence of the compound of the present invention.
  • the pharmaceutical composition or formulation preferably comprises a compound of the present invention in an amount sufficient to inhibit HIF-l ⁇ .
  • the pharmaceutical composition can comprise more than one active ingredient, such as more than one compound of the present invention, or a compound of the present invention in combination with another pharmaceutically active agent or drug.
  • the carrier can be any suitable carrier.
  • the carrier is a pharmaceutically acceptable carrier.
  • the carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the active compound(s), and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical composition, the compounds of the present inventive methods can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • compositions described herein for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compound(s) and one which has no detrimental side effects or toxicity under the conditions of use.
  • injectable formulations are among those formulations that are preferred in accordance with the present invention.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). It is preferred that such injectable compositions be administered intravenously or, in the context of the treatment of cancer, intratumorally (within the tumor) or peritumorally (near the outside of the tumor).
  • Topical formulations are well-known to those of skill in the art. Such • formulations are particularly suitable in the context of the present invention for application to the skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • an inert base such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • the present inventive compound alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the present inventive compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4- methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose,
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionie detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-b-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionie surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the present inventive compounds, or compositions comprising such compounds can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the compounds of the present invention can be used for any purpose.
  • the compounds of the present invention have an affinity for Hsp90, and can be used to inhibit Hsp90, for example, in a cell such as a mammalian cell or a human cell.
  • Such method can be used, for instance, in vitro for research or diagnostic purposes, or in vivo, wherein the cell is in a host such as a mammal or a human, for the diagnosis, prevention, or treatment of a disease, such as cancer.
  • In vivo activity can be measured by any suitable method known in the art. Suitable methods include, for example, a hollow fiber assay (HFA), xenograft testing and the like, as well as combinations of such testing.
  • HFA hollow fiber assay
  • a preferred method of determining in vivo activity is a hollow fiber assay, as described in M.G. Hollingshead et al., In Vivo Cultivation of Tumor Cells in Hollow Fibers, (57)2 Life Sci. 131-141 (1995).
  • a hollow fiber assay is used as a preliminary screen to identify compounds having moderate to prominent anti-cancer activity.
  • compounds which exhibit significant positive results are considered to have moderate to prominent anti-cancer activity.
  • HFA can be used in conjunction with other testing methods, such as xenograft testing, to provide more evidence as to the in vivo anti-cancer activity of compounds and, thus, their suitability for treatment of a particular disease.
  • geldanamycin and derivatives thereof known prior to the present invention have approximately an equal affinity for both Hsp90 and Grp94 (i.e., they inhibit Hsp90 and Grp94 with about the same effectiveness).
  • the compounds of the present invention desirably have a selective affinity for Hsp90 over Grp94, and can be used to selectively inhibit Hsp90.
  • Further provided by the present invention is a method of selectively inhibiting Hsp90 without substantially inhibiting Grp94 in a cell.
  • the method comprises administering to a cell comprising Hsp90 and Grp94 a compound of the present invention in an amount sufficient to inhibit Hsp90 without substantially inhibiting Grp94, whereupon Hsp90 is selectively inhibited.
  • the method can be used with any type of cell, such as a mammalian cell, preferably, a human cell.
  • a compound of the present invention can be administered to such cell in vitro, or in vivo, wherein the cell is in a host such as a mammal, preferably, a human.
  • Methods of administering a compound of the present invention to a cell in vitro or in vivo are known in the art, and include by way of example those previously described.
  • the present method of selectively inhibiting Hsp90 does not inhibit Grp94 at all or inhibits Grp94 in a de minimus amount.
  • the present method can be used to inhibit Hsp90 without substantially inhibiting Grp94, wherein the Grp94 activity level is about 50% or more, preferably about 60% or more, about 70% or more, about 80% or more, about 90% or more or even about 95% or more (e.g., 97% or more), as compared to the Grp94 activity level in the absence of a compound of the present invention, or any inhibitor of the Grp94 activity level.
  • a compound of the present invention is administered to a cell that expresses ErbB2 in the absence of the compound of the present invention, or to a host including such cells, in an amount sufficient to reduce or eliminate the expression of ErbB2 protein.
  • the expression of ErbB2 is preferably reduced by at least about 20% , by at least about 30%, such as at least about 40% (e.g., at least about 50%), by at least about 70%, (e.g., at least about 80%), or even by at least about 90%, or completely, as compared to expression of ErbB2 in the absence of the compound of the present invention.
  • HIF-l ⁇ is a transcription factor that is recognized as a pro-survival factor in many types of cancer, and some tumor cells rely on HIF-l ⁇ to stimulate many cellular processes, such as the transcriptional activation of erythropoietin, inducible nitric oxide synthase, and vascular endothelial growth factor (VEGF), which is used to produce new blood vessel growth in tumor tissues.
  • VEGF vascular endothelial growth factor
  • HIF-l ⁇ is rapidly degraded by a ubiquitin ligase complex, which binds to the HJF-l ⁇ protein via a protein known as VHL.
  • VHL is absent from the cell or is mutated such that lacks normal activity towards the HIF-l ⁇ protein (e.g., cannot bind to the HIF-l ⁇ protein)
  • the HIF-l ⁇ protein accumulates in the cell.
  • Lack of VHL activity often exists, for example, in the context of a metastatic disease (e.g., metastatic cancer), and is often prevalent in renal cell carcinomas.
  • the compounds of the present invention can be used to reduce the level of HIF-l ⁇ in a cell, thereby inhibiting the activity of HIF-l ⁇ , by destabilizing the protein and/or degrading or stimulating the degradation of HIF-l ⁇ .
  • the compounds of the present invention also can be used to inhibit HIF-l ⁇ by interfering with the transcriptional activity of HIF-l ⁇ independent of its effect on the stability of the protein.
  • the mechanism by which the compounds of the present invention inhibit HIF-l ⁇ appears to be independent of the presence of oxygen or VHL.
  • the compounds of the present invention can be used to inhibit HIF-l ⁇ in hypoxic cells comprising VHL, or in normoxic or hypoxic cells lacking VHL or lacking normal VHL activity towards HIF-l ⁇ .
  • the present invention therefore, provides a method of inhibiting HIF- 1 ⁇ in a cell.
  • This method comprises administering to a cell comprising HIF-l ⁇ a compound of the present invention in an amount sufficient to inhibit HIF-l ⁇ .
  • the method can be used with any type of cell, such as a mammalian cell, preferably, a human cell.
  • a compound of the present invention can be administered to such cell in vitro, or in vivo, wherein the cell is in a host such as a mammal, preferably, a human.
  • a compound of the present invention is, desirably, administered to a cell comprising HIF-l ⁇ in an amount sufficient to inhibit HJF-1 ⁇ such that the activity of the HIF-1 ⁇ in the cell is reduced by at least about 20%, preferably by at least about 30%, such as by at least about 40% (e.g., by at least about 50%), by at least about 70% (e.g., at least about 80%), or even by at least about 90%, or completely, as compared to the activity of HIF-l ⁇ in the cell in the absence of the compound of the present invention.
  • Methods by which the inhibition of the HIF-l ⁇ protein activity can be measured are generally known in the art.
  • known methods can be used to measure and compare the level of HJF-1 ⁇ produced in a cell, the half-life of HIF-1 ⁇ in a cell, and/or the transactivation activity of HIF-l ⁇ in a cell, in the presence and absence of a compound of the present invention in order to evaluate the level of HIF-1 ⁇ activity.
  • inventive method of inhibiting Hsp90, method of selectively inhibiting Hsp90 without substantially inhibiting Grp94, and method of inhibiting HIF-l ⁇ can be used for any purpose. Such uses -will be apparent to those of ordinary skill in the art.
  • the inhibition or selective inhibition of Hsp90, and/or the inhibition of HIF-l ⁇ can be used to investigate, for instance, intra- or intercellular molecular activity, such as the interactions between the proteins and compounds discussed herein and their relation to the diagnosis, treatment, and prevention of cancer.
  • Such methods are also advantageous for applications in vivo.
  • the activity of each of the Hsp90 and HIF-l ⁇ proteins has been linked to cancer cell proliferation, and the inhibition of such proteins is useful in the diagnosis, treatment, or prevention of cancer or tumors in a host.
  • the selective inhibition of Hsp90 without substantially inhibiting Grp94 is believed to provide other special advantages in vivo.
  • Grp94 is localized to the endoplasmic reticulum and performs, or assists, certain protein processing functions. Without wishing to be bound by any particular theory, it is believed that the inhibition of Grp94 causes certain undesirable side effects without any substantial anti-cancer or anti-tumor effect. It is further believed that the use of geldanamycin or its known derivatives, which have approximately equal affinity for Hsp90 and Grp94, leads to unwanted side effects for these reasons. Thus, it is believed that the present method of selectively inhibiting Hsp90 can be used advantageously in vivo without substantially disrupting the function of Grp94, for example, in the treatment, diagnosis, or prevention of cancer.
  • the present invention further provides a method of treating or preventing cancer in a host.
  • the method comprises administering a compound of the present invention to a host in an amount sufficient to treat or prevent cancer in the host, whereupon the cancer of the host is treated or prevented.
  • the host includes cells comprising Hsp90 and Grp94, and the compound is administered in an amount sufficient to inhibit Hsp 90 without substantially inhibiting Grp94.
  • the cells of the host further comprise ErbB2 proteins, and the compound is administered in an amount sufficient to deplete substantially ErbB2 proteins in the cells.
  • the method of the present invention can also be used to treat or prevent cancer in a host that includes cells comprising HIF-1 ⁇ , wherein a compound of the present invention is administered in an amount sufficient to inhibit HIF-1 ⁇ .
  • the method of the present invention is especially useful to treat or prevent cancer in a host, as described herein, wherein the cancer is a metastatic cancer, such as a renal cell carcinoma.
  • the host is a mammal, in particular a human.
  • the method of treating cancer using the compound of the present invention can be made more effective by administering one or more other anticancer compounds along with one or more other compounds of the present invention.
  • anticancer compounds include, but are not limited to, all of the known anticancer compounds approved for marketing in the United States and those that will become approved in the future. See, for example, Table 1 and Table 2 of Boy d, Current Therapy in Oncology, Section I. Introduction to Cancer Therapy (J.E. Niederhuber, ed.), Chapter 2, by B.C. Decker, Inc., Philadelphia, 1993, pp. 11-22.
  • these other anticancer compounds include doxorubicin, bleomycin, vincristine, vinblastine, VP-16, VW-26, cisplatin, carboplatin, procarbazine, and taxol for solid tumors in general; alkylating agents, such as BCNU, CCNU, methyl-CCNU and DTIC, for brain or kidney cancers; and antimetabolites such as 5-FU and methotrexate for colon cancer.
  • compositions comprising the present inventive compound to an animal, such as a mammal, in particular a human, are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the herein-described methods are exemplary and are in no way limiting.
  • the dose administered to an animal should be sufficient to prevent cancer, delay its onset, or slow (or stop) its progression.
  • dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body weight of the animal.
  • the size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound and the desired physiological effect.
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present inventive method will typically involve the administration of about 0.1 to about 100 mg of one or more of the compounds described above per kg body weight.
  • This product was further purified by silica gel column chromatography using 5% MeOH/CH 2 Cl 2 as eluent (2.4 g) to form an intermediate compound of Geldanamycin N-(tert- butoxycarbonyl) glycinate.
  • Trifluoroacetic acid (7.5 mL) (Aldrich, Lot No. PZ06421KZ) was added to a clear solution of the intermediate compound described above (1.4 g, 1.95 mmol) in dry methylene chloride (15 mL) (Burdick & Jackson, Lot No. BE512) at room temperature. The resulting clear red solution was stirred at room temperature for 30 minutes, evaporated and pumped (0.1 mmHg) to dryness. While still at room temperature, the residue was triturated with ether (30 mL) and filtered to give a yellow powder (1.2 g), which was subsequently dissolved in methylene chloride (30 mL).
  • the resulting solution was then washed with 5% NaHCO 3 (10 mL X 2) and with brine (10 mL X 1), dried using MgSO 4 and filtered.
  • the pH of the solution was then adjusted to ca. 3 by the addition of methanolic HCl. After adjusting the pH, the filtrate was evaporated and pumped (0.1 mmHg) to dryness. The remaining residue was dissolved in methylene chloride (2 mL) and subsequently diluted with dilute ethereal HCl (50 mL) at room temperature. This mixture was stirred for 30 minutes and filtered to give prepurified product.
  • the salt (1 g, 1.53 mmol) was redissolved in methylene chloride (50 mL). The solution was then washed with 1% NaHCO 3 (25 mL X 1) and water (25 mL X 2), dried using MgSO and filtered. The filtrate was adjusted to pH 3 with dilute methanolic HCl to produce a red solution, which was subsequently evaporated and pumped (0.1 mmHg) to dryness. The residue was then dissolved in methylene chloride (2 mL), seeded and diluted with dilute ethereal HCl (30 mL). The mixture was stirred at room temperature for 30 minutes and filtered to produce 4.8 g of purified Geldanamycinglycinate hydrochloride. The water-solubility of the purified product was greater than 3 mg/ml.
  • the column was eluted with methylene chloride (100 mL) followed by methylene chloride-methanol (97:3, 200 mL; 96:4, 100 mL; 95:5, 100 mL; 94:6, 100 mL; 93:7, 100 mL; 92:8, 100 mL).
  • the product-containing fractions were combined and concentrated in an aspirator to give a residue which was rechromatographed over silica gel (27 g) using methylene chloride- methanol (97:3, 100 mL; 193:7, 200 mL; 96:4, 200 mL; 95:5, 100 mL; 94:6, 200 mL; 93:7, 200 mL) as eluant.
  • the product-containing fractions were combined and concentrated in an aspirator to give a residue, which was dissolved in a mixture of methylene chloride (3 mL) and diethyl either (5 mL).
  • the filtrate was diluted with diethyl ether (60 mL) with stirring, then refrigerated for 1 hour.
  • the solid was collected by filtration, washed with diethyl ether (3 X 8 mL), and dried at 64 °C/0.1 mmHg for 4 hours to give 960 mg (39%) of pure target compound as a purple solid.
  • the water solubility of the purified product was greater than 3 mg/mL.
  • the pH of the aqueous layer was adjusted from a pH of 9 to pH of 3 by the addition of solid sodium bisulfate monohydrate (59.0 g, 0.43 mol), and the pH-adjusted solution was extracted three times with ether (450 ml aliquots).
  • the combined ether extract was washed with water (200 ml), dried using MgSO , and concentrated.
  • the residue (87.9 g) was dissolved in ether (100 ml).
  • the solution was diluted with petroleum ether (50 ml), seeded with product from a previous preparation and cooled in an ice-water bath. After the product crystallized, more petroleum ether (250 ml) was added and the mixture was stirred at 0 °C for 1 hour.
  • the white solid was collected by filtration to give 71.9 g of 4-(tert- butoxycarbonyl)-aminobutyric acid (mp 50-52 °C).
  • geldanamycin (70.0 g) was processed in this manner to give an additional 43.7 g of the intermediate product.
  • the unreacted geldanamycin was recovered according to the following process. The mother liquor recovered from the production of the 1 l-(4-(tert-butoxycarbonyl) aminobutyrate-geldanamycin was concentrated to a small volume (100 ml) and the mixture was filtered. The solid was washed twice with ethanol (10 ml aliquots), three times with petroleum ether (20 ml aliquots), and air-dried to yield unreacted geldanamycin (24.4 g) contaminated with 1 l-(4-(tert-butoxycarbonyl) aminobutyrate-geldanamycin. All of the recovered geldanamycin was recycled to give additional intermediate (13.9 g, mp 235 °C), with acceptable elemental analysis.
  • the partial solution was diluted slowly with petroleum ether (800 ml). The mixture was stirred at room temperature for 1 hour. The yellow powder was collected by filtration and dried at 25.°C and at 0.1 mmHg for 10 hours to give 54.2 g of pure ll-(4-aminobutyrate)- geldanamycin hydrochloride. The water solubility of the purified product was about 3 mg/ml.
  • the solution was filtered through a celite pad, and the filtrate was diluted with hexanes (30 mL) (Fisher Scientific, Lot No. 963814) and refrigerated for 3 hours.
  • the solid was then collected by filtration and washed with hexanes (10 mL X 2), then air-dried to give 260 mg of target compound as a purple crystalline solid.
  • additional target compound was prepared in two batches and added to the first batch.
  • Compounds A-E were tested in a hollow fiber assay for in vivo activity.
  • the compounds were tested against a standard panel of 12 human tumor cell lines including NCI-H23, NCI-H522, MDA-MB-231, MDA-MB-435, SW-620, COLO 205, LOX IMVI, UACC-62, OVCAR-3, OVCAR-5, U251 and SF-295.
  • the cell lines were cultivated in RPMI-1640 containing 10% FBS and 2 mM glutamine. On the day preceding hollow fiber preparation, the cells were given a supplementation of fresh medium to maintain log phase growth. For fiber preparation, the cells were harvested by standard trypsinization technique and resuspended at the desired cell density.
  • the cell suspensions were flushed into 1 mm polyvinylidene fluoride (PVDF) hollow fibers (MW exclusion of 500,000 Da) and subsequently heat-sealed at .2 cm intervals.
  • PVDF polyvinylidene fluoride
  • the samples generated from these seals were placed into tissue culture medium and incubated at 37 °C in 5% CO 2 for 24-48 hours prior to implantation.
  • a total of 3 different tumor cell lines were prepared for each experiment so that each mouse received 3 intraperitoneal implants (1 of each tumor cell line) and 3 subcutaneous implants (1 of each tumor cell line).
  • samples of each tumor cell line were quantitated for viable cell mass by a stable endpoint MTT assay so that the time 0 cell mass was known.
  • MTT assay the fibers were incubated in 6-well plates (1-6 fibers/well) with 3 mL of pre-warmed (37 °C) complete medium containing MTT (1 mg/mL) (Sigma) for 4 hours at 37 °C in 5% CO 2 .
  • the MTT solution was aspirated and the fibers were washed with 2 mL of saline containing 2.5% protamine sulfate overnight at 4 °C.
  • a second wash was performed with 2 mL of saline containing 2.5% protamine sulfate, and the fibers were maintained at 4 °C for a minimum of 2 hours.
  • the fibers were then removed from the protamine sulfate, individually wiped, placed in a 24- well plate (1 fiber/well), cut in half and dried overnight in a biosafety hood.
  • DMSO was added (0.25 mL) to each well and the plates were rotated for 4 hours at room temperature. The extracted samples were transferred to 96-well plates and the OD was determined at 540 nm. From these spectrophotomeric measurements, the cytostatic and cytocidal capacities of the test compound were assessed.
  • mice were treated with Compounds A-E on day 3 or 4 following fiber implantation and continuing once daily for a total of 4 doses.
  • the compounds were assessed by intraperitoneal injection at 2 dose levels with 3 mice/dose/experiment.
  • Vehicle controls consisted of 6 mice receiving the compound diluent only.
  • the fibers were collected from the mice on the day following the fourth compound treatment and subjected to the stable endpoint MTT assay.
  • the optical density of each sample was determined spectrophotometrically at 540 nm and the mean of each treatment group was calculated.
  • the percent net cell growth in each treatment group was determined and compared to the percent net cell growth in the vehicle treated controls.
  • Compounds were scored on the basis of several hollow fiber assay criteria, including (1) a reduction in net cell growth of 50% or greater in 10 of the 48 possible test combinations; (2) a reduction in net cell growth of 50% or greater in a minimum of 4 of the 24 distant site combinations (SC score); and/or (3) cell kill of 1 or more cell lines in either implant site (reduction in the viable cell mass below the level present at the start of the experiment).
  • IP intraperitoneal
  • SC subcutaneous
  • a hollow fiber assay was conducted with Compounds A-E, as described above.
  • Compounds A-E were mixed with saline and tween 80 (0.05%) to obtain the dosage levels indicated in Table 1. Optimal dosage levels were determined from previous toxicity studies and therefore the dosages used represent the upper range that can be administered to a host without inducing toxic effects. The compounds were administered once daily for four days via intraperitoneal injection. After four days, the hollow fibers were removed from the mice and subjected to the MTT assay as described above. The percent cell growth inhibition was calculated [(l-(% treated net growth/%) control net growth))* 100] and an HFA score was assigned to Compounds A-E on the basis of this calculation, as indicated in Table 1.
  • This example demonstrates the relative affinity of GA and a compound of the present invention (1 l-(4-aminobutyrate)-geldanamycin hydrochloride) for Hsp90.
  • Hsp90 binding affinity was analyzed through competitive binding between the soluble test drug (GA or 1 l-(4-aminobutyrate)-geldanamycin hydrochloride) and immobilized GA resin.
  • SKBR3 cells purchased from American Type Culture Collection, Manassas, VA
  • DMEM medium supplemented with 10% FCS, 2 mM glutamine, 1 mM Hepes, and 100 U penicillin and streptomycin, for 24-48 hours.
  • Cell lysates were clarified by centrifugation at 14,000 rpm (4 °C) for 15 minutes.
  • This example demonstrates the relative affinity of GA and a compound of the present invention (1 l-(4-aminobutyrate)-geldanamycin hydrochloride) for Grp94.
  • Grp94 binding affinity was determined through competitive binding between the soluble test drug (GA or 1 l-(4-aminobutyrate)-geldanamycin hydrochloride) and [3H]- N-ethylcarboxamidoadenosine (NECA). GA and NECA are known to share the same binding site on Grp94.
  • the assay solutions contained 5 mg of purified Grp94, 20 nM of NECA, 50 mM Tris buffer (pH at 7.5), and concentrations of GA or 1 l-(4-aminobutyrate)- geldanamycin hydrochloride ranging from 0.03 ⁇ M to 100 ⁇ M.
  • the assay solutions were incubated on ice for 1 hour.
  • Grp94 was then collected on polyethyleneimine-treated glass filters and washed twice with 4 ml of ice-cold 50 mM Tris (pH at 7.5). The washed Grp94 was dried and counted in a scintillation counter to determine the amount of NECA-bound Gr ⁇ 94.
  • SRKB3 cells as used in Example 2, were incubated with increasing concentrations of GA or 1 l-(4-aminobutyrate)-geldanamycin hydrochloride. Cells were lysed and ErbB2 content of the total lyses were determined by SDS-PAGE gel electrophoresis followed by Western Blotting for ErbB2. For purposes of comparison, the same procedure was carried out using GA.

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Abstract

L'invention concerne un dérivé de geldanamycine de formule générale (I) et des procédés in vitro et in vivo pour l'inhibition sélective de Hsp90 dans une cellule sans pour autant sensiblement inhiber Grp94, procédés consistant à administrer à une cellule renfermant Hsp90 et Grp94, ou à un hôte comprenant ces cellules renfermant Hsp90 et Grp94, respectivement, le dérivé de geldanamycine en quantité suffisante pour inhiber Hsp90 sans sensiblement inhiber Grp94. L'invention concerne également des procédés permettant d'inhiber HIF-1α dans une cellule, consistant à administrer à une cellule renfermant HIF-1α le dérivé de geldanamycine en quantité suffisante pour inhiber HIF-1α, ainsi qu'une méthode de traitement ou de prévention du cancer chez un hôte, qui consiste à lui administrer un dérivé de geldanamycine en quantité suffisante pour traiter ou prévenir le cancer.
PCT/US2001/044172 2000-11-06 2001-11-06 Derives de geldanamycine utiles dans le traitement du cancer WO2002036574A1 (fr)

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GB2384428A (en) * 2002-01-29 2003-07-30 Thromb X Nv Inhibitors of HIF
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6872715B2 (en) 2001-08-06 2005-03-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005053744A1 (fr) * 2003-11-26 2005-06-16 Entelos, Inc. Traitement de la polyarthrite rhumatoide au moyen d'antagonistes du facteur 1$g(a) inductible par hypoxie
EP1631267A4 (fr) * 2003-05-30 2006-07-12 Kosan Biosciences Inc Methode de traitement de maladies mettant en oeuvre des agents inhibant hsp90 conjointement avec des antimetabolites
US7241754B2 (en) 2003-06-13 2007-07-10 Kosan Biosciences, Inc. 2-Desmethyl ansamycin compounds
US7259156B2 (en) 2004-05-20 2007-08-21 Kosan Biosciences Incorporated Geldanamycin compounds and method of use
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
US7589174B2 (en) 2003-05-12 2009-09-15 The Children's Hospital Of Philadelphia GRP94-based compositions and methods of use thereof
WO2009112615A1 (fr) 2008-03-11 2009-09-17 Fundación De La Comunidad Valenciana, Centro De Investigación Principe Felipe Composition pharmaceutique permettant d'inhiber le facteur de transcription induit par l'hypoxie. modulateurs des processus pathologiques de l'angiogenèse, de l'oncogenèse, de l'inflammation, de l'apoptose et thérapie cellulaire
US8466140B2 (en) 2007-09-10 2013-06-18 University Of Massachusetts Mitochondria-targeted anti-tumor agents

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Cited By (21)

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US7405208B2 (en) 2001-08-06 2008-07-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
US6872715B2 (en) 2001-08-06 2005-03-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
GB2384428A (en) * 2002-01-29 2003-07-30 Thromb X Nv Inhibitors of HIF
US7589174B2 (en) 2003-05-12 2009-09-15 The Children's Hospital Of Philadelphia GRP94-based compositions and methods of use thereof
EP1631267A4 (fr) * 2003-05-30 2006-07-12 Kosan Biosciences Inc Methode de traitement de maladies mettant en oeuvre des agents inhibant hsp90 conjointement avec des antimetabolites
US7241754B2 (en) 2003-06-13 2007-07-10 Kosan Biosciences, Inc. 2-Desmethyl ansamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
EP1682514A4 (fr) * 2003-11-12 2008-07-16 Kosan Biosciences Inc Composes 11-o-methylgeldanamycine
JP2007510718A (ja) * 2003-11-12 2007-04-26 コーザン バイオサイエンシス インコーポレイテッド １１−ｏ−メチルゲルダナマイシン化合物
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
JP4717003B2 (ja) * 2003-11-12 2011-07-06 コーサン バイオサイエンシーズ， インコーポレイテッド １１−ｏ−メチルゲルダナマイシン化合物
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005053744A1 (fr) * 2003-11-26 2005-06-16 Entelos, Inc. Traitement de la polyarthrite rhumatoide au moyen d'antagonistes du facteur 1$g(a) inductible par hypoxie
US7259156B2 (en) 2004-05-20 2007-08-21 Kosan Biosciences Incorporated Geldanamycin compounds and method of use
US7378407B2 (en) 2004-05-20 2008-05-27 Kosan Biosciences Incorporated Geldanamycin compounds and method of use
WO2008044041A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
WO2008044045A1 (fr) 2006-10-12 2008-04-17 Astex Therapeutics Limited Combinaisons pharmaceutiques
US8466140B2 (en) 2007-09-10 2013-06-18 University Of Massachusetts Mitochondria-targeted anti-tumor agents
US9987294B2 (en) 2007-09-10 2018-06-05 University Of Massachusetts Mitochondria-targeted anti-tumor agents
WO2009112615A1 (fr) 2008-03-11 2009-09-17 Fundación De La Comunidad Valenciana, Centro De Investigación Principe Felipe Composition pharmaceutique permettant d'inhiber le facteur de transcription induit par l'hypoxie. modulateurs des processus pathologiques de l'angiogenèse, de l'oncogenèse, de l'inflammation, de l'apoptose et thérapie cellulaire

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