Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • 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
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
• • 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
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • 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
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
  • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• a cell's DNA is replicated and then divided into two new cells.
• the process of separating the newly replicated chromosomes into the two forming cells involves spindle fibers constructed with microtubules, which themselves are formed by long chains of smaller protein subunits called tubulins. 15 Spindle microtubules attach to replicated chromosomes and pull one copy to each side of the dividing cell. Without these microtubules, cell division is not possible.
• Microtubules therefore are among the most important sub-cellular targets of anticancer chemotherapeutics because they are present in all cells and are necessary for mitotic, interphase and cell maintenance functions (e.g. intracellular transport, 0 development and maintenance of cell shape, cell motility, and possibly distribution of molecules on cell membranes).
• Compounds that interact with tubulin can interfere with the cell cycle by causing tubulin precipitation and sequestration, thereby interrupting many important biologic functions that depend on the microtubular class of subcellular organelles. Therefore, such compounds can 5 potentially inhibit the proliferation of tumor cell lines derived from various organs. See, e.g., Bacher et al. (2001) Pure Appl. Chem. 73:9 1459-1464 and Rowinsky & Donehower (1991) Pharmac. Ther. 52:35-84.
• Indibulin is a synthetic small molecule tubulin inhibitor with significant antitumor activity in vitro and in vivo. It destabilizes microtubules in tumor cells, as well as in a cell-free system.
• the binding site of Indibulin does not appear to overlap with the tubulin-binding sites of the well-characterized microtubule- destabilizing agents vincristine or colchicine.
• the molecule selectively blocks cell cycle progression at metaphase. Improved methods of using indibulin to treat hyperproliferative disorders would be useful.
• the invention relates to a method for the treatment of cancer, comprising administering a indolyl-3-glyoxylic acid derivative.
• the indolyl-3-glyoxylic acid derivative is a N-substituted indole-3- glyoxylamide or a pharmaceutically acceptable salt thereof.
• the indolyl-3-glyoxylic acid derivative is indibulin.
• the cancer is selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer.
• the cancer is selected from renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer.
• the invention relates to a method for the treatment of a cancer selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer comprising administering an indolyl-3- glyoxylic acid derivative, preferably indibulin.
• a cancer selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer comprising administering an indolyl-3- glyoxylic acid derivative, preferably indibulin.
• One aspect of the invention relates to combination therapy, wherein an indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof is administered with one or more other therapeutic agents and the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• Such combination treatment may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
• Another aspect of the invention provides combination therapy, wherein indibulin or a pharmaceutically acceptable salt thereof is administered with one or more other therapeutic agents and the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• Such combination treatment may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
• the indolyl-3-glyoxylic acid derivative is conjointly administered with one or more chemotherapeutic agents, hormonal therapeutic agents, targeted therapy, radiotherapy, immunotherapy, gene therapy, or surgery, preferably a chemotherapeutic.
• chemotherapeutic agents hormonal therapeutic agents, targeted therapy, radiotherapy, immunotherapy, gene therapy, or surgery, preferably a chemotherapeutic.
• Such conjoint therapy may be as a single formulation of the two or more agents (e.g., tablet, pill, or liquid formulation) or the agents may be formulated separately.
• Another aspect of the invention relates to methods for the treatment of cancer, comprising administering an indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof in combination with another therapeutic agent, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• the cancer is selected from breast, lung, ovarian, and prostate cancer.
• Another aspect of the invention relates to methods for the treatment of cancer, comprising administering indibulin or a pharmaceutically acceptable salt thereof in combination with another therapeutic agent, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• the cancer is selected from breast, lung, ovarian, and prostate cancer.
• kits comprising an indolyl-3- glyoxylic acid derivative or a pharmaceutically acceptable salt thereof and another therapeutic agent.
• kits comprising indibulin and another therapeutic agent.
• Figure IA shows the dose response curve of the indibulin-erlotinib combination as compared to the agents used alone with A549 NSLC cells.
• Figure IB shows the IC 40 (ng/mL) concentrations of indibulin and erlotinib used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 4O (ng/mL) concentration is set to 100%.
• Figure 2 A shows the dose response curve of the indibulin-carboplatin combination as compared to the agents used alone with A549 NSLC cells.
• Figure 2B shows the IC 70 (ng/mL) concentrations of indibulin and carboplatin used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 7O (ng/mL) concentration is set to 100%.
• Figure 3 A shows the dose response curve of the indibulin-5FU combination as compared to the agents used alone with MCF7 cells.
• Figure 3B shows the IC 60 (ng/mL) concentrations of indibulin and 5-FU used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 6O (ng/mL) concentration is set to 100%.
• Figure 4A shows the dose response curve of the indibulin-vinorelbine combination as compared to the agents used alone with MCF7 cells.
• Figure 4B shows the IC 6O (ng/mL) concentrations of indibulin and vinorelbine used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 60 (ng/mL) concentration is set to 100%.
• Figure 5 A shows the dose response curve of the indibulin-tamoxifen combination as compared to the agents used alone with MCF7 cells.
• Figure 5B shows the IC 60 (ng/mL) concentrations of indibulin and tamoxifen used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 60 (ng/mL) concentration is set to 100%.
• Figure 6A shows the dose response curve of the indibulin-paclitaxel (Taxol) combination as compared to the agents used alone with MCF7 cells.
• Figure 6B shows the IC 84 (ng/mL) concentrations of indibulin and paclitaxel (Taxol) used alone and in combination, wherein the Y-scale is normalized such that each single agent IC 84 (ng/mL) concentration is set to 100%.
• Figure 7 shows that colchicine, nocodazole and podophyllotoxin compete with 3H-indibulin for tubulin binding while vinblastine and taxol do not compete.
• Figure 8 shows that indibulin inhibits about 40% of 3H-colchicine binding, nocodazole and podophyllotoxin completely inhibit 3H colchicine binding, while taxol and vinblastine have no effect.
• Figure 9 shows the effect of indibulin on polymerization of purified calf and adult bovine brain tubulin.
• Figure 10 shows that orally administered indibulin inhibits growth of MCF7 breast cancer in xenografts.
• Figure 11 shows that orally administered indibulin inhibits growth of U87 glioblastoma xenografts.
• Figure 12 shows that orally administered indibulin inhibits growth of murine renal cell carcinoma RENCA.
• the invention relates to a method for the treatment of cancer, comprising administering an indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof.
• the indolyl-3- glyoxylic acid derivative is indibulin.
• the cancer is selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer.
• the cancer is selected from renal cell carcinoma, breast cancer, ovarian cancer, prostate cancer, vulvar cancer, glioblastoma, and lung cancer.
• the invention relates to a method for the treatment of a cancer selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer comprising administering an indolyl-3- glyoxylic acid derivative, preferably indibulin.
• a cancer selected from adenoid cystic carcinoma, renal cell carcinoma, breast cancer, vulvar cancer, glioblastoma, and lung cancer comprising administering an indolyl-3- glyoxylic acid derivative, preferably indibulin.
• One aspect of the invention relates to combination therapy, wherein an indolyl-3-glyoxylic acid derivative, such as indibulin, or a pharmaceutically acceptable salt thereof is administered with one or more other therapeutic agents and the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• an indolyl-3-glyoxylic acid derivative such as indibulin
• a pharmaceutically acceptable salt thereof is administered with one or more other therapeutic agents and the combination shows efficacy that is greater than the efficacy of either agent being administered alone (e.g., synergistic or additive antitumor effect).
• Such combination treatment may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
• an indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof suitable for use in the methods disclosed herein is a compound disclosed in US Patent No. 6,008,231, 6,232,327, or 6,693,119, the specifications of which are hereby incorporated herein by reference in their entirety.
• the indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof has a structure of Formula (I)
• R is selected from hydrogen; (Ci-C 6 )-alkyl, where the alkyl group is optionally mono- or polysubstituted with a phenyl ring which is optionally mono- or polysubstituted with halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, carboxyl, carboxyl esterif ⁇ ed with Ci-C 6 -alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy, benzyloxy or a benzyl group which is mono- or polysubstituted on the phenyl moiety with (Ci-C 6 )-alkyl groups, halogen or trifluoromethyl; benzyloxycarbonyl; tertiary-butoxycarbonyl; and acetyl;
• Ri is selected from a phenyl ring, which is optionally mono- or polysubstituted with (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (Ci-C 6 )-alkylamino, (Ci-C 6 )- alkoxycarbonylamino, carboxyl, or by carboxyl esterified with Ci-C 6 -alkanol; a pyridine structure of the Formula (II)
• Ri in the case in which R is hydrogen, benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or benzyl, may be the acid radical of a natural or unnatural amino acid (e.g. ⁇ -glycyl, ⁇ -sarcosyl, ⁇ -seryl, ⁇ -phenylalanyl, ⁇ -histidyl, ⁇ -prolyl, ⁇ - arginyl, ⁇ -lysyl, ⁇ -asparagyl or ⁇ -glutamyl), where the amino groups of the respective amino acids may be protected or unprotected, wherein suitable protecting groups include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, or acetyl, and in the case where Ri is asparagyl or glutamyl, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester of a Ci- C 6
• R and Ri can further form, together with the nitrogen atom to which they are bonded, a piperazine ring of the Formula (III) or a homopiperazine ring, provided R
• R 7 is selected from alkyl; phenyl which is optionally mono- or polysubstituted with (Ci-C 6 )-alkyl, (Ci-C 6 )-alkoxy, halogen, nitro, amino or by (C
• R 2 is selected from hydrogen; (C]-C 6 )-alkyl, wherein the alkyl group is optionally mono- or polysubstituted with halogen, phenyl (wherein the phenyl is optionally mono- or polysubstituted with halogen, (Ci-C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, carboxyl, carboxyl esterified with Ci-C ⁇ -alkanol, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy), 2-quinolyl (optionally mono- or polysubstituted with halogen, (Ci-C 4 )-alkyl or (Ci-C 4 )-alkoxy), or 2-, 3- or 4-pyridyl (optionally mono- or polysubstituted with halogen, (Ci-C 4 )-alkyl or (Ci-C 4 )-alkoxy); aroy
• R 3 and R 4 are identical or different and are selected from hydrogen, (Ci-C 6 )- alkyl, (C 3 -C 7 )-cycloalkyl, (Ci-C 6 )-alkanoyl, (Ci-C 6 )-alkoxy, halogen, benzyloxy, nitro, amino, (Ci-C 4 )-mono or dialkyl-substituted amino, (Ci-C 6 )- alkoxycarbonylamino and (Ci-C 6 )-alkoxycarbonylamino-(Ci-C 6 )-alkyl;
• Z is O or S.
• R 2 is selected from (Ci-C 6 )-alkyl, wherein the alkyl group is optionally mono- or polysubstituted with halogen, phenyl (wherein the phenyl is optionally mono- or polysubstituted with halogen, (C
• the indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof are of the general Formula (IV):
• Y and Z are, independently, NR, O, or S, in which R is hydrogen, alkyl, aryl, acyl, cycloalkenyl, heterocycloalkenyl, alkenyl, cycloalkenyl, heterocycloalkenyl, aminocarbonyl,
• R 3 and R 3 ' are, independently,alkyl, aryl, heteroaryl, or X is NR 8 R 9 , wherein, R 8 and R 9 are, independently, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, acyl, aryl, or heteroaryl;
• A, B, C and D are, independently, nitrogen or carbon, provided if A is nitrogen, R 4 is absent, and if A is carbon, R 4 is either hydrogen, halogen, or alkyl; if B is nitrogen, R 5 is absent, and if B is carbon, R 5 is hydrogen, halogen, or alkyl; if C is nitrogen, R6 is absent, and if C is carbon, R 6 is hydrogen, halogen, or alkyl; if D is nitrogen, R 7 is absent, and if D is carbon, then R 7 is hydrogen, halogen, or alkyl;
• Ri is hydrogen, alkyl, aralkyl, acyl, or aryl
• R 2 is hydrogen, alkyl, acyl , aryl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, cycloalkoxycarbonyl, heterocycloalkoxycarbonyl, alkenyloxycarbonyl, cycloalkenyloxycarbonyl and heterocycloalkenyloxycarbonyl.
• Ri is selected from alkyl, alkylaryl, acyl, and aryl.
• Ri is a substituted benzyl group, more preferably a halogenated benzyl group (2-, 3-, or (4-halophenyl)methyl), and most preferably a (4-chlorophenyl)methyl group.
• R 4 , R 5 , R 6 , and R 7 are hydrogen atoms.
• either R 3 or R 3 ' is hydrogen and the remaining substituent (R 3 or R 3 ') is a pyridinyl group (pyridine ring). More preferably, either R 3 or R 3 ' is hydrogen and the remaining substituent (R 3 or R 3 ') is a 4-pyridinyl group.
• the indolyl-3-glyoxylic acid derivative is administered in combination with another therapeutic agent selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel (Taxol), tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.
• another therapeutic agent selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel (Taxol), tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.
• the indolyl-3-glyoxylic acid derivative such as indibulin or a pharmaceutically acceptable salt thereof, is administered in combination with another therapeutic agent selected from erlotinib, carboplatin, 5- fluorouracil, paclitaxel, tamoxifen, and vinorelbine.
• another therapeutic agent selected from erlotinib, carboplatin, 5- fluorouracil, paclitaxel, tamoxifen, and vinorelbine.
• the combination is synergistic.
• the combination is additive.
• the indolyl-3-glyoxylic acid derivative is administered in combination with another therapeutic agent selected from vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), taxanes (e.g., paclitaxel and docetaxel), epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (e
• the indolyl-3-glyoxylic acid derivative is administered in combination with another therapeutic agent selected from a tubulin binding agent, a kinase inhibitor (e.g., a receptor tyrosine kinase inhibitor), an anti- metabolic agent, a DNA synthesis inhibitor, and a DNA damaging agent.
• a kinase inhibitor e.g., a receptor tyrosine kinase inhibitor
• an anti- metabolic agent e.g., a DNA synthesis inhibitor
• DNA synthesis inhibitor e.g., a DNA synthesis inhibitor
• a DNA damaging agent e.g., a DNA damaging agent.
• an indolyl-3-glyoxylic acid derivative such as indibulin is administered in combination with another therapeutic agent selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.
• indibulin is administered in combination with another therapeutic agent selected from erlotinib, carboplatin, 5- fluorouracil, paclitaxel (Taxol), tamoxifen, and vinorelbine.
• the combination is synergistic. In certain alternative embodiments, the combination is additive. In certain embodiments, indibulin is administered in combination with another therapeutic agent selected from vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), taxanes (e.g., paclitaxel and docetaxel), epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents; antiproliferative/
• indibulin is administered in combination with another therapeutic agent selected from a tubulin binding agent, a kinase inhibitor (e.g., a receptor tyrosine kinase inhibitor), an anti-metabolic agent, a DNA synthesis inhibitor, and a DNA damaging agent.
• a kinase inhibitor e.g., a receptor tyrosine kinase inhibitor
• an anti-metabolic agent e.g., a receptor tyrosine kinase inhibitor
• DNA synthesis inhibitor e.g., a DNA synthesis inhibitor
• DNA damaging agent e.g., a DNA damaging agent.
• Another aspect of the invention relates to methods for the treatment of cancer, comprising administering an indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent, wherein the combination is beneficial to efficacy, optionally additive or synergistic.
• the invention relates to methods for the treatment of a cancer selected from lung, breast, ovarian, and prostate cancer.
• the invention relates to methods for the treatment of a cancer selected from lung and breast cancer.
• the indolyl-3- glyoxylic acid derivative or a pharmaceutically acceptable salt thereof has a structure of Formula (I).
• Another aspect of the invention relates to methods for the treatment of cancer, comprising administering indibulin or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent, wherein the combination is beneficial to efficacy, optionally additive or synergistic.
• the invention relates to methods for the treatment of a cancer selected from lung, breast, ovarian, and prostate cancer.
• the invention relates to methods for the treatment of a cancer selected from lung and breast cancer.
• treatment is an approach for obtaining beneficial or desired results, including clinical results.
• beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
• Treatment can also mean prolonging survival as compared to expected survival in the absence of receiving treatment, or as compared to a control patient or patients not receiving treatment.
• kits comprising an indolyl-3- glyoxylic acid derivative or a pharmaceutically acceptable salt thereof and another therapeutic agent.
• the other therapeutic agent is selected from erlotinib, carboplatin, 5-fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.
• the other therapeutic agent is selected from erlotinib, carboplatin, 5-fluorouracil, paclitaxel, tamoxifen, and vinorelbine.
• the indolyl-3-glyoxylic acid derivative or a pharmaceutically acceptable salt thereof has a structure of Formula (I).
• Another aspect of the invention relates to a kit, comprising indibulin or a pharmaceutically acceptable salt thereof and another therapeutic agent.
• the other therapeutic agent is selected from erlotinib, carboplatin, 5- fluorouracil, capecitabine, paclitaxel, tamoxifen, vinorelbine, cisplatin, gemcitabine, estramustine, doxorubicin, vinblastine, etoposide, and prednisolone.
• the other therapeutic agent is selected from erlotinib, carboplatin, 5- fluorouracil, paclitaxel, tamoxifen, and vinorelbine.
• Administration of the indolyl-3-glyoxylic acid derivative may precede or follow the other therapeutic agent by intervals ranging from minutes to days.
• the indolyl-3-glyoxylic acid derivative and the other therapeutic agent may be administered within about 1 minute, about 5 minutes, > about 10 minutes, about 30 minutes, about 60 minutes, about 2 hours, about 4 hours, about 6 hours, 8 hours, about 10 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, or even about 48 hours or more of one another.
• administration of the indolyl-3-glyoxylic acid derivative and the other therapeutic agent will be within about 1 minute, about 5 minutes, about 30 minutes, or even about 60 minutes of one another.
• the indolyl-3-glyoxylic acid derivative and the other therapeutic agent may be administered according to different dosing schedules (e.g., indibulin, for example may be administered once a day while the other therapeutic agent may be administered only once every three weeks) such that in some instances administration of the indolyl-3-glyoxylic acid derivative and the other therapeutic agent will be within about 60 minutes of one another, while in other instances, administration of the indolyl-3-glyoxylic acid derivative and the other therapeutic agent will be within days or even weeks of one another.
• indibulin for example may be administered once a day while the other therapeutic agent may be administered only once every three weeks
• the term "regimen” is a predetermined schedule of one or more therapeutic agents for the treatment of a cancer. Accordingly, when a therapeutic agent is administered “alone,” the regimen does not include the use of another therapeutic agent for the treatment of cancer.
• the indolyl-3-glyoxylic acid derivative, such as indibulin is administered once daily for fourteen days every three weeks. In certain embodiments, such dosing is by oral administration of, for example, a liquid or capsule.
• a single dose comprises from about 20 to about 80 mg.
• a dose is about 100 to about 250 mg, or even more.
• a daily dose may be about 100 to 2000 mg, about 250 to about 2000 mg, or even about 500 to about 2000 mg.
• a daily dose may be greater than or equal to 500 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, or even 2500 mg.
• the indolyl-3-glyoxylic acid derivative such as indibulin may be administered, e.g., as an oral dosage form (e.g., as described in the preceding paragraph), every two days, every three days, every other day, daily, twice daily, or even three times daily, or in any other regular regimen, e.g. continuous treatment.
• Such administration may be for a duration of three weeks, four weeks, five weeks or more, such as six months, one year, two years, or more.
• continuous treatment means a dose in which the patient goes no more than one or at most two consecutive days without a dose for as long as there is a perceived benefit, e.g. such as six months, one year, two years, five years, or even more.
• the indolyl-3-glyoxylic acid derivative, such as indibulin is administered twice daily as an oral dosage form.
• the indolyl-3-glyoxylic acid derivative such as indibulin
• the indolyl-3-glyoxylic acid derivative is administered as a continuous treatment, preferably as an oral dosage form.
• the continuous treatment comprises administration of an oral dosage form twice daily.
• Suitable oral dosage forms include, but are not limited to, capsules, such as hard gelatin capsules.
• each dose comprises about 400 mg of the indolyl-3-glyoxylic acid derivative, such as indibulin, administered twice daily.
• the indolyl-3-glyoxylic acid derivative, such as indibulin is administered with food. In certain such embodiments administration with food may increase bioavailability.
• combinations as described herein may be synergistic in nature, meaning that the therapeutic effect of the combination of the indolyl-3- glyoxylic acid derivative and the other therapeutic agent(s) is greater than the sum of the individual effects.
• combinations as described herein may be additive in nature, meaning that the therapeutic effect of the combination of the indolyl-3- glyoxylic acid derivative and the other therapeutic agent(s) is greater than the effect of each agent individually (i.e., the therapeutic effect is the sum of the individual effects).
• Compounds described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art.
• the compounds may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), or drop infusion preparations.
• the active ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
• a binder such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
• the compounds described herein may be administered as a particulate composition, preferably an aqueous suspension of nanoparticles with at least one surfactant selected from ionic surfactants, non-ionic surfactants, zwitterionic surfactants, biologically derived surfactants, amino acids and their derivatives and combinations thereof.
• a particulate composition preferably an aqueous suspension of nanoparticles with at least one surfactant selected from ionic surfactants, non-ionic surfactants, zwitterionic surfactants, biologically derived surfactants, amino acids and their derivatives and combinations thereof.
• Such particulate compositions may be administered in any suitable way, including, but not limited to orally or parenterally.
• one or more compounds described herein are present in the composition in an amount from about 0.01% to about 20% (w/v), preferably from about 0.055 to about 15% w/v, or even from about 0.1% to about 10% w/v.
• the particles will vary in size from about 15 nm to 50 microns, preferably from about 50 nm to 10 microns, or even from about 50 nm to 2 microns.
• the particles When the particles are prepared for administration by injection, it is preferred that the have a particle size of less than about 5 microns (microparticles) or even less than about 2 microns (nanoparticles).
• Particulate compositions described herein are also described in WO 2006/052712, the disclosure of which is incorporated herein in its entirety.
• Suitable surfactants for coating the particles in the present invention can be selected from ionic surfactants, nonionic surfactants, zwitterionic surfactants, phospholipids, biologically derived surfactants or amino acids and their derivatives.
• Ionic surfactants can be anionic or cationic.
• the surfactants are present in the compositions in an amount of from about 0.01% to 10% w/v, and preferably from about 0.05% to about 5% w/v.
• Suitable anionic surfactants include but are not limited to: alkyl sulfonates, aryl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, phosphatidic acid and their salts, sodium carboxymethylcellulose, bile acids and their salts (e.g., salts of cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid), and calcium carboxymethylcellulose, stearic acid and its salts (e.g., sodium and calcium stearate), phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dioctyl sodium sulfosuccinate (DOSS), dialkylesters of sodium sulfosuccinic acid, sodium lauryl
• Suitable cationic surfactants include but are not limited to: quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, cetyl pyridinium chloride, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quaternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium
• Suitable nonionic surfactants include but are not limited to: polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glyceryl esters, glycerol monostearate, polyethylene glycols, polypropylene glycols, polypropylene glycol esters, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene- polyoxypropylene copolymers, poloxamers, poloxamines, methylcellulose, hydroxycellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides, starch, starch derivatives, hydroxyethylstarch, polyvinyl alcohol, polyvinylpyrrolidone, triethanolamine stearate, amine oxides, dextran, glycerol, gum acacia, cholesterol, traga
• Zwitterionic surfactants are electrically neutral but possess local positive and negative charges within the same molecule. The net charge on the molecule may depend on the pH, and therefore at low pH some zwitterionic surfactants may act as cationic surfactants while at high pH they may also act an anionic surfactants. Suitable zwitterionic surfactants include but are not limited to zwitterionic phospholipids.
• phospholipids include phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such as dimyristoylglycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero- phosphoethanolamine (DPPE), distearoyl-glycero-phosphoethanolamine (DSPE), and dioleolyl-glycerophosphoethanolamine (DOPE), pegylated phospholipids, PEG- phosphatidylcholine, PEG-diacyl-glycero-phosphoethanolamine, PEG- phosphatidylethanolamine, PEG-diacyl-glycerophosphoethanolamine, PEG- dimyristoyl-glycero-phosphoethanolamine, PEG-dipalmitoylglycero- phosphoethanolamine, PEG-distearoyl-glycero-phosphoethanolamine, PEG- dioleolyl-glycero-phosphoethanolamine,
• phospholipids that include anionic and zwitterionic phospholipids may be employed in this invention.
• Such mixtures include but are not limited to lysophospholipids, egg or soybean phospholipid or any combination thereof.
• Suitable biologically derived surfactants include, but are not limited to: lipoproteins, gelatin, casein, lysozyme, albumin, casein, heparin, hirudin, or other proteins.
• a preferred ionic surfactant is a bile salt, and a preferred bile salt is sodium deoxycholate.
• a preferred nonionic surfactant is a polyalkoxyether, and preferred polyalkoxyethers are polyoxyethylene-polyoxypropylene triblock copolymers such as Poloxamer 188 and Poloxamer 407.
• Another preferred surfactant is a lipid in which a polyalkoxyether is covalently attached to a lipid through an ether linkage.
• a preferred surfactant of this class is a pegylated phospholipid.
• Another preferred surfactant is a pegylated phospholipid methyl ether (for example, mPEG-DSPE).
• the particles are suspended in an aqueous medium further including a pH adjusting agent.
• pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, tris buffer, mono-, di- tricarboxylic acids and their salts, citrate buffer, phosphate, glycerol-1 -phosphate, glycercol-2-phosphate, acetate, lactate, tris(hydroxymethyl)aminomethane, aminosaccharides, mono-, di- and trialkylated amines, meglumine (N-methylglucosamine), and amino acids.
• the aqueous medium may additionally include an osmotic pressure adjusting agent, such as but not limited to glycerin, a monosaccharide such as dextrose, a disaccharide such as sucrose, trehalose and maltose, a trisaccharide such as raffmose, and sugar alcohols such as mannitol and sorbitol.
• an osmotic pressure adjusting agent such as but not limited to glycerin, a monosaccharide such as dextrose, a disaccharide such as sucrose, trehalose and maltose, a trisaccharide such as raffmose, and sugar alcohols such as mannitol and sorbitol.
• the aqueous medium of the particle suspension composition is removed to form dry particles.
• the method to remove the aqueous medium can be any method known in the art.
• One example is evaporation.
• Another example is freeze-drying or lyophilization.
• the dry particles may then be formulated into any acceptable physical form including, but not limited to, solutions, tablets, capsules, suspensions, creams, lotions, emulsions, aerosols, powders, incorporation into reservoir or matrix devices for sustained release (such as implants or transdermal patches), and the like.
• the aqueous suspension of the present invention may also be frozen to improve stability upon storage. Freezing of an aqueous suspension to improve stability is disclosed in the commonly assigned and co-pending U. S Patent Application Serial No.
• compositions comprise an aqueous suspension of particles of tubulin inhibitor present at 0.05% to 10% w/v, the particles are coated with 0.05% to 5% w/v of an ionic surfactant (e.g., deoxycholate) or a zwitterionic surfactant (e.g., mPEG-DSPE), and 0.05% to 5% w/v polyalkoxyether (for example, Poloxamer 188), and glycerin added to adjust osmotic pressure of the formulation.
• an ionic surfactant e.g., deoxycholate
• a zwitterionic surfactant e.g., mPEG-DSPE
• polyalkoxyether for example, Poloxamer 188
• the particle suspensions of the present invention can be prepared by methods known to those skilled in the art and those methods described below.
• compounds as disclosed herein may be administered as a pharmaceutical formulation for oral administration, wherein the formulation comprises a granulate containing micronized indolyl-3-glyoxylic acid derivative, such as indibulin, having a particle size of less than 20 ⁇ m for at least 99 vol.-% of the particles, at least one hydrophilic surfactant, and one or more additional capsulation excipients.
• a pharmaceutical formulation for oral administration wherein the formulation comprises a granulate containing micronized indolyl-3-glyoxylic acid derivative, such as indibulin, having a particle size of less than 20 ⁇ m for at least 99 vol.-% of the particles, at least one hydrophilic surfactant, and one or more additional capsulation excipients.
• the micronized indolyl-3-glyoxylic acid derivative has a particle size of less than 10 ⁇ m for at least 90 vol.% of the particles, less than 10 ⁇ m for at least 99 vol.% of the particles. In certain preferred embodiments, the micronized indolyl-3-glyoxylic acid derivative has a mean particle size in the range of 2 to 4 ⁇ m.
• the pharmaceutical formulation comprises a indolyl-3-glyoxylic acid derivative in an amount of about 10 to about 50 weight %, the at least one hydrophilic surfactant in an amount of about 1 to about 10 weight %, and one or more capsulation excipients in an amount of about 40 to about 80 weight %, the three constituents always adding up to 100 weight % of said pharmaceutical formulation.
• the hydrophilic surfactant is not subject to any particular limitation as long as it is capable of acting as an oil-in-water surfactant.
• the one or more hydrophilic surfactant(s) is/are selected from the group consisting of polysorbates, poloxamers, cremophors and polyalkylene glycols. Any type of polysorbate can be employed, but particularly the polysorbate is selected from polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, more preferred from polysorbate 80. Further, any type of poloxamers can be employed. Poloxamers are surfactant-like block polymers having a central polypropylene glycol moiety which on both terminal ends is connected to a macrogol moiety.
• Typical poloxamers suited for the present invention are poloxamers 188 and 407, particularly poloxamer 188.
• Cremophors are non-ionic emulsif ⁇ ers obtained by causing ethylene oxide to react with castor oil particularly in a molar ratio of about 35 moles to 1 mole.
• Other common names are polyoxyethyleneglyceroltriricinoleate 35 or polyoxyl 35 castor oil.
• a typical cremophor is for example Cremophor ® EL supplied by BASF AG, Germany.
• As capsulation excipients those which are common in the art can be suitably used in the present invention.
• those capsulation excipients can comprise cellulose such as microcrystalline cellulose or a derivative thereof, gelatin, starch, particularly corn starch, and highly disperse silicon dioxide (aerosil).
• the capsulation excipients comprise a mixture of microcrystalline cellulose, gelatin, corn starch and aerosil.
• corn starch and microcrystalline can serve as a filling mass and degradants.
• Highly disperse silicon dioxide (aerosil) acts in turn to make the mass fluent.
• Gelatin usually serves as an adhesive to get homogeneous granules.
• the granules constituting said pharmaceutical formulation are covered by an outer phase composed of a mixture comprising starch, particularly corn starch, highly dispersed silicon dioxide and magnesium stearate.
• an outer phase composed of a mixture comprising starch, particularly corn starch, highly dispersed silicon dioxide and magnesium stearate.
• the pharmaceutical formulation is a tablet prepared using said pharmaceutical formulation or a capsule filled with said pharmaceutical formulation, respectively.
• the pharmaceutical formulation of the indolyl-3-glyoxylic acid derivative may be based on micronization of the compound combined with a granulation procedure using a hydrophilic surfactant (e.g., polysorbate, poloxamer, cremophor) and common capsulation excipients (e.g., cellulose, starch, highly disperse silicon dioxide, etc).
• a hydrophilic surfactant e.g., polysorbate, poloxamer, cremophor
• common capsulation excipients e.g., cellulose, starch, highly disperse silicon dioxide, etc.
• the indolyl-3-glyoxylic acid derivative and the other therapeutic agent may be in the same form (e.g., both may be administered as tablets or both may be administered intravenously) while in certain alternative embodiments, the indolyl-3-glyoxylic acid derivative and the other therapeutic agent may be in different forms (e.g. one may be administered as a tablet while the other is administered intra
• the precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc.
• physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication
• route of administration etc.
• the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
• phrases "pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
• pharmaceutically acceptable salt refers to the relatively nontoxic, inorganic and organic acid addition salts of the inhibitor(s). These salts can be prepared in situ during the final isolation and purification of the inhibitor(s), or by separately reacting a purified inhibitor(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, trifluoroacetate, citrate, embonate, methanesulfonate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, succinate, tosylate, citrate, malonate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, gluconate, glucouronate, glucoheptonate, 2-hydroxyethansulfonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like.
• sulfate bisulfate
• phosphate nitrate
• acetate trifluoroacetate
• citrate embonate
• methanesulfonate valerate
• oleate palmitate
• stearate la
• the inhibitors useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
• pharmaceutically acceptable salts refers to the relatively nontoxic inorganic and organic base addition salts of an inhibitor(s). These salts can likewise be prepared in situ during the final isolation and purification of the inhibitor(s), or by separately reacting the purified inhibitor(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
• Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethyl enediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT
• Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of an inhibitor(s) as an active ingredient.
• lozenges using a flavored basis, usually sucrose and acacia or tragacanth
• a composition may also be administered as a bolus, electuary, or paste.
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption
• pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered inhibitor(s) moistened with an inert liquid diluent.
• Tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• opacifying agents include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and e
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
• Suspensions in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• compositions of this invention suitable for parenteral administration comprise one or more inhibitors(s) in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
• Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents, such as sugars
• delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsule matrices of inhibitor(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection, and infusion.
• systemic administration means the administration of a ligand, drug, or other material other than directly into the central nervous system, such that it enters the patient's system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
• compositions of the present invention administered to a patient will follow general protocols for the administration of chemotherapeutics, taking into account the toxicity, if any. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies or adjunct cancer therapies, as well as surgical intervention, may be applied in combination with the described arsenical agent.
• the inhibitor(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the monolayer assay determines the in vitro antitumor activity of test compounds and their capacity to inhibit survival and proliferation of established tumor cell lines. These effects can be determined by establishing the number of viable cells based on measuring the DNA content using propidium iodide.
• indibulin and the other agents were tested separately each at ten different concentrations for their antitumor activity in cell lines MCF-7 (breast), A549 (NSCLC), SKOV3 (ovarian), and PC3 (prostate). Between 5,000 and 10,000 cells were seeded in 96 well plates on Day 0 and the compounds were added 1 day later and incubated for 4 days. All compounds were tested in half-log steps at concentrations indicated in Table 1. The activity was assessed by their IC 50 and IC 70 values.
• A549 cells were grown and exposed to indibulin and erlotinib as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (erlotinib:indibulin ratio 208:1):
• A549 cells were grown and exposed to indibulin and carboplatin as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (carboplatin:indibulin ratio 303:1):
• MCF-7 cells were grown and exposed to indibulin and 5FU as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (5FU:indibulin ratio 10.9:1):
• MCF-7 cells were grown and exposed to indibulin and vinorelbine as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (vinorelbine: indibulin ratio 0.016:1):
• MCF-7 cells were grown and exposed to indibulin and tamoxifen as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (tamoxifen ⁇ ndibulin ratio 100:1):
• MCF-7 cells were grown and exposed to indibulin and paclitaxel as described above and DNA content measurements with propidium iodide was used to determine the number of viable cells. Concentrations for single agents and combination were as follows (paclitaxel :indibulin ratio 0.27:1):
• Inhibitory Constants (IC) for combination treatment are substantially lower than those for single agents (see Table 4 below).
• tubulin binding site of indibulin tritium labeled indibulin was incubated with purified bovine brain tubulin in the presence or absence of various tubulin binding agents. As shown in Figures 7 and 8, 3H- indibulin or 3H-colchicine were incubated with biotin-labeled calf brain tubulin. Where indicated, a 200-fold molar excess of cold competitor was added. Tubulin heterodimers were then precipitated with streptavidin-coated SPA beads and bound radioactivity was determined. "No tubulin" indicates non-specifically bound radioactivity measured in the absence of biotin-labeled tubulin.
• Figure 7 shows that colchicine, nocodazole and podophyllotoxin (all bind to the same tubulin binding site) compete with 3H-indibulin for tubulin binding while inblastine and taxol do not compete.
• Figure 8 shows that indibulin inhibits about 40% of 3H-colchicine binding. Nocodazole and podophyllotoxin completely inhibit binding while taxol and vinblastine have no effect.
• Tubulin from neuronal tissue is post-translationally modified and the degree of modification increases during neuronal development.
• Calf brain neuronal tubulin and tubulin from other tissues differ in their post-translational modifications from that of adult bovine brain.
• Polymerization of purified calf brain tubulin was inhibited by increasing concentrations of indibulin, with an IC 50 value of about 0.25 ⁇ M and a maximum inhibition of 90% as shown in Figure 9.
• Tubulin polymerization is given as % over DMSO control.
• Polymerization of bovine brain tubulin was inhibited by indibulin only by 25% at the highest dose tested. In contrast vincristine or colchicine inhibited both, calf and bovine brain tubulin polymerization to a similar extent.
• the inability of indibulin to bind to neuronal tubulin supports the observed lack of neurotoxicity with indibulin in preclinical studies as well as in Phase 1 clinical trials.
• Example 3 Indibulin does not disrupt axonal microtubules of rat pheochromocytoma
• PC 12 PC 12 cells.
• the outgrowth of neurites of PC 12 was induced by NGF for 5-6 days.
• Cells were subsequently treated with DMSO, indibulin or colchicine for 24 h (2 x IC 50 concentration each).
• Microtubules within the neurites were visualized by immunostaining with an antibody recognizing acetylated (axonal) tubulin, leaving the cell bodies unstained.
• DMSO control and indibulin treated cells show identical staining patterns, indicating that indibulin did not affect axonal microtubules.
• treatment with colchicine resulted in a strongly reduced and diffuse staining of microtubules indicating that microtubules were partially disrupted by colchicine.
• indibulin was tested in a series of cancer models, including human glioblastoma xenograft (U 87).
• Figure 1 1 shows that orally administered indibulin inhibits growth of U87 glioblastoma xenografts.
• 5 x 106 U87 glioblastoma cells were implanted subcutaneously in immunodeficient nu/nu mice. Treatment started when tumor weight was about 0.15 g (Day 0).
• indibulin inhibits growth of murine renal cell carcinoma RENCA.
• 1.5 x 106 RENCA cells were injected into the subcapsular space of the kidney through a flank incision (Day 1).
• Indibulin was orally administered daily at indicated doses from Day 1 - 20 (5x/week).
• mice were sacrificed and weight and volume of primary tumors, weight and number of metastases of the lung and metastasis formation in the abdominal lymph nodes determined. Reduction in tumor volume and weight by indibulin (D-24851) was statistically significant. Metastasis data not shown; there was a trend in reduction of number of lung metastases but was not statistically significant.
• TNP-470 has shown anti-tumor activity in different animal models and is well established for its use in RENCA.
• indibulin was tested in a series of cancer models, including murine renal cell carcinoma (RENCA), DMBA induced mammary carcinoma in rats, human ovarian xenograft (SK-OV-3), human prostate cancer xenograft (PC-3), human vulvar squamous cell carcinoma xenograft (A431), human glioblastoma xenograft (U 87), human mamma carcinoma (MCF-7), and human lung carcinoma (A 549). In all models indibulin demonstrated strong and statistically significant anti-tumor activity.
• RENCA murine renal cell carcinoma
• SK-OV-3 human ovarian xenograft
• PC-3 human prostate cancer xenograft
• A431 human vulvar squamous cell carcinoma xenograft
• U 87 human glioblastoma xenograft
• MCF-7 human mamma carcinoma
• lung carcinoma A 549
• references and publications are hereby incorporated by reference.
• References incorporated herein by reference in their entirety include, but are not limited to, WO 2006/133835, WO 2006/052712, US 2004/0171668, and 2003/0195360.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Inorganic Chemistry (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (4)

Applications Claiming Priority (10)

Publications (1)

Family

ID=39307954

Family Applications (1)

Country Status (6)

Cited By (3)

Families Citing this family (1)

Citations (5)

Family Cites Families (16)

• 2007
  • 2007-11-27 EP EP07853153A patent/EP2091532A1/en not_active Withdrawn
  • 2007-11-27 JP JP2009539288A patent/JP2010511041A/ja active Pending
  • 2007-11-27 AU AU2007325797A patent/AU2007325797B2/en not_active Ceased
  • 2007-11-27 CA CA002670778A patent/CA2670778A1/en not_active Abandoned
  • 2007-11-27 US US11/986,844 patent/US20080241274A1/en not_active Abandoned
  • 2007-11-27 WO PCT/US2007/024438 patent/WO2008066807A1/en not_active Ceased
• 2012
  • 2012-11-20 US US13/681,828 patent/US20130084345A1/en not_active Abandoned
• 2013
  • 2013-08-02 US US13/958,160 patent/US20140193519A1/en not_active Abandoned

Patent Citations (5)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events