WO2004044219A2 - Composes de xanthene destines a la chimiotherapie du cancer - Google Patents

Composes de xanthene destines a la chimiotherapie du cancer Download PDF

Info

Publication number
WO2004044219A2
WO2004044219A2 PCT/US2003/035418 US0335418W WO2004044219A2 WO 2004044219 A2 WO2004044219 A2 WO 2004044219A2 US 0335418 W US0335418 W US 0335418W WO 2004044219 A2 WO2004044219 A2 WO 2004044219A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
independently
group
ras
mammal
Prior art date
Application number
PCT/US2003/035418
Other languages
English (en)
Other versions
WO2004044219A3 (fr
Inventor
Neal C. Birnberg
Quing Weng
Hong Liu
Joseph Avruch
John Kyriakis
Original Assignee
Mercury Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mercury Therapeutics, Inc. filed Critical Mercury Therapeutics, Inc.
Priority to AU2003291268A priority Critical patent/AU2003291268A1/en
Publication of WO2004044219A2 publication Critical patent/WO2004044219A2/fr
Publication of WO2004044219A3 publication Critical patent/WO2004044219A3/fr

Links

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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the ras gene was discovered as an oncogene of the Harvey (rasH) and Kirsten (rasK) rat sarcoma viruses.
  • rasH Harvey
  • rasK Kirsten
  • characteristic mutations in the cellular ras gene have been associated with many different types of cancers.
  • These mutant alleles which render ras constitutively active, have been shown to transform cells, such as the murine cell line NIH 3T3, in culture.
  • the ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate
  • GDP GTP-bound state of ras that is active.
  • GTPase-activating protein GAP
  • Ras proto-oncogene requires a functionally intact raf-1 proto-oncogene in order to transduce growth and differentiation signals initiated by receptor and non-receptor tyrosine kinases in higher eukaryotes. Activated Ras is necessary for the activation of the c-raf-
  • the invention includes a method of treating cancer in a mammal, comprising administering to said mammal a compound represented by Structural Formula (I):
  • Ri and R are independently -ORio
  • R 3 and t are independently -H, -ORio, halogen, or a substituted or unsubsituted alkyl group
  • R 5 -R 8 are independently -H, -ORio, halogen, or a substituted or unsubstituted alkyl group
  • R 9 is a polar functional group
  • Rio is -H, a substituted or unsubsituted alkyl group, or a substituted or unsubstituted acyl group;
  • the invention is a method of inhibiting cellular proliferation (e.g., excessive or unwanted cellular proliferation) in a mammal or a method of inhibiting the interaction of Raf protein or fragments, mutants or 80%- 100% homologs thereof with Ras protein or fragments, mutants or 80%- 100% homologs thereof in a mammal, comprising administering to the mammal one of the compounds disclosed herein.
  • cellular proliferation e.g., excessive or unwanted cellular proliferation
  • Fig. 1 shows initial hit structures from the Ras-Raf screen.
  • Fig. 2 shows the 3,6-dihydroxy-9-carboxyxanthene core, and its oxidized and reduced forms.
  • Fig. 3 shows a scanning library of structurally-related compounds.
  • Fig. 4 shows potential substitution patterns of the 3,6-dihydroxy-9-carboxyxanthene core.
  • Fig. 5 shows expression and purification of the K-Ras protein.
  • Fig. 6 shows the structure of Raf and truncated Raf fusion proteins in used the assays described herein.
  • Fig. 7 shows the purification of biotinylated Raf-50-220 proteins.
  • Fig. 8 shows the configuration and optimization of the Ras-Raf protein-protein interaction assay.
  • Fig. 9 shows the results of the high throughput screen for inhibitors of Ras-Raf protein- protein interaction.
  • Fig. 10 shows the phosphorylatoin of ERK following serum withdrawal and refeeding in human colon tumor cell line HCT116.
  • hydrocarbyl group is an alkylene or arylene group, i.e., -(CH2) X - or -(CH 2 ) ⁇ C 6 H (CH 2 ) x -, where x is a positive integer (e.g., from 1 to about 30), preferably between 6 and about 30, more preferably between 6 and about 15.
  • the carbon chain of the hydrocarbyl group may be optionally interrupted with one or more ether (-0-), thioether
  • R D are independently -H, alkyl, substituted alkyl, phenyl, or substituted phenyl.
  • R a and R ⁇ can be the same or different, but are preferably the same.
  • hydrocarbyl groups include butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, dodecylene, 4-oxaoctylene, 4-azaoctylene, 4-thiaoctylene, 3,6-dioxaoctylene, 3,6-diazaoctylene, and 4,9- dioxadodecane.
  • An "aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched, or cyclic and typically contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • Aliphatic groups include lower alkyl groups, lower alkylene and lower alkenylene groups, which include Cl-24 (preferably Cl-C 12) straight chained or branched saturated hydrocarbons.
  • An alkyl group is a saturated hydrocarbon in a molecule that is bonded to one other group in the molecule through a single covalent bond from one of its carbon atoms.
  • Examples of lower alkyl groups include methyl, ethyl, w-propyl, wo-propyl, n-butyl, sec-butyl and tert-butyl.
  • An alkoxy group is an alkyl group where an oxygen atom connects the alkyl group and one other group.
  • An alkylene group is a saturated hydrocarbon in a molecule that is bonded to two other groups in the molecule through single covalent bonds from two of its carbon atoms. Examples of lower alkylene groups include methylene, ethylene, propylene, .-?o-propylene
  • An alkenylene group is similar to an alkylene group, but contains one or more double bonds.
  • acyl group is an alkyl, alkenyl or alkynyl group having a carbonyl group located at the terminus of the group that connects to the remainder of the molecule.
  • acyl groups are an acetyl (CH 2 C(O)-) and a benzyl (C 6 H 5 C(0)-) group.
  • Aromatic or aryl groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.
  • Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • Examples include 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3- indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazole, 2-benzooxazole, 2-benzimidazole, 2- quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl and 3-isoindolyl.
  • Phenyl is a preferred aromatic group.
  • Arylene is an aromatic ring(s) moiety in a molecule that is bonded to two other groups in the molecule through single covalent bonds from two of its ring atoms. Examples include phenylene -[-( 4)-], thienylene [-(C4H2S)-] and furanylene [-(C4H2O)-].
  • Suitable substituents on an hydrocarbyl, aliphatic, acyl, aromatic or benzyl group may include, for example, halogen
  • R is independently -H, an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group, and is preferably -H, a lower alkyl group, a benzylic group or a phenyl group.
  • a substituted benzylic group or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent.
  • a substituted aliphatic group can also have a benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent.
  • a substituted aliphatic, substituted aromatic or substituted benzyl group can have more than one substituent.
  • a preferred substituent on an aliphatic group is -OH.
  • Polar functional groups include halogen, alcohol, amine, nitrile, nitro, sulfonic acid, sulfinic acid, sulfenic acid, carboxylic acid, thiol, aldehyde, ester, amide, acid chloride, carbamate, carbonate, thiol acid, dithiocarbamate, dithiocarbonate, as well as pharmaceutically acceptable salts thereof.
  • Examples of pharmaceutically acceptable counteranions in a salt include sulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, proprionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, fumarate, maleate, benzoate, sulfonate, phenylacetate, citrate, lactate, glycolate, tartrate, carbonate, bicarbonate and the like.
  • Examples of pharmaceutically acceptable cations in a salt include metal cations, such as alkali (e.g., Li, Na, K), alkaline earth (e.g., Ca, Mg), transition metal (e.g., Cu, Fe, Zn) or heavy metal (e.g., Bi) cations.
  • metal cations such as alkali (e.g., Li, Na, K), alkaline earth (e.g., Ca, Mg), transition metal (e.g., Cu, Fe, Zn) or heavy metal (e.g., Bi) cations.
  • Other suitable cations include the acids of the anions listed in the previous paragraph.
  • Effective amounts of a compound disclosed herein to be administered will be determined on an individual basis, and will be determined at least in part, by consideration of the individual's size, the severity of symptoms to be treated and the result sought. As used herein, an effective amount refers to an appropriate amount of active ingredient to obtain therapeutic effect and can be determined by standard pharmaceutical procedures in cell cultures or experimental
  • the compound can be administered alone or in a pharmaceutical composition comprising the compound, a pharmaceutically acceptable carrier, and optionally, one or more additional drugs.
  • the compound can be administered in a manner including but not limited to, for example, topically, ophthalmically, vaginally, orally, buccally, intranasally, rectally, transdermally, parenterally (e.g., intramuscular injection, intraperitoneal injection, subcutaneous injection) or pulmonarily.
  • parenterally e.g., intramuscular injection, intraperitoneal injection, subcutaneous injection
  • the form in which the compound is administered includes but is not limited to, for example, powder, tablet, capsule, solution, or emulsion, depends in part on the route by which it is administered.
  • the compound may be aerosolized or nebulized.
  • Suitable carriers and diluents will be immediately apparent to persons skilled in the art.
  • These carrier and diluent materials include, for example, gelatin, albumin, lactose, starch, magnesium stearate preservatives (stabilizers), melting agents, emulsifying agents, salts and buffers.
  • examples of pharmaceutically acceptable carriers include, for example, commercially available inert gels, or liquids supplemented with albumin, methyl cellulose or a collagen matrix. Typical of such formulations are ointments, creams and gels. The effective amount can be administered in a series of doses separated by appropriate time intervals such as minutes or hours.
  • the xanthene core presents a number of sites for the generation of structural diversity.
  • Suitable linkers include 1,2, and 3 carbon aliphatic linkers; aromatic linkers containing carboxyl substitution at position 2', 3', and 4'; cycloalkyl linkers containing carboxyl substitution at position 2', 3', and 4'; and a 2' benzyl linker.
  • positions 1, 2, 4, 5, 7, and 8 can be substituted with electron withdrawing (CI), electron donating (OMe), and neutral (Me) substituents at these positions.
  • Specific substitution patterns include substitution of CI, Me, and OMe at position 1, 2, and 4 as well as 2,7-symmetric-disubstitution and 4,5-dihydroxyl substitutions.
  • AlphaScreen detection technology is based on a signal generated by the forced proximity of two types of 100 nM beads, so-called Acceptor and Donor beads. This proximity is mediated by interactions between molecules under study that are bound to each bead. When the two beads are brought within 100 nM of each other in a stable intermolecular complex, a unique light signature is produced. Employing this methodology, Applicants developed an assay for the interaction between Ras and Raf-1, and to monitor the inhibition of this interaction by small molecules. The AlphaScreen assay is further described below.
  • each protein In order to configure a high throughput assay sensitive to small molecules that interfere with the intermolecular interaction between Ras oncogene products and c-Raf, each protein must first be expressed and purified in stable fashion to greater than 95% purity as evidenced by polyacrylamide gel electrophoresis.
  • the full length, GTPase-deficient valine-12 substituted K-Ras containing 6 His residues at the N-terminus was expressed in insect SF9 cells using a baculovirus vector and purified by affinity chromatography on a Ni-NTA-cellulose column.
  • a typical yield in this expression system is approximately 20 ⁇ g of purified K-Ras from a 15 cm diameter plate containing 10 7 SF9 cells.
  • ten 10 cm plates of cells are infected at a time with a yield of -200 ⁇ g of >95% pure K-Ras protein.
  • a polyacrylamide gel detailing the purification of V12-K-Ras from baculovirus infected cells is shown in Fig. 5.
  • Sf9 cells were infected (MOI of 5) with a recombinant baculovirus encoding
  • Ras protein was purified by affinity chromatography on a Ni-NTA-agarose column and eluted with increasing concentrations of imidazole. Each eluted fraction was 2 ml with 20 ⁇ l loaded in each lane. The material in the 350 mM and 500 mM fractions was pooled for use in the Ras-Raf protein-protein interaction assay.
  • Amino acids 39-220 constitute the Ras binding domain of Raf-1. This domain can be subdivided into two regions. The amino terminal segment, amino acids 50-150, contains a high affinity site (Kd ⁇ 10 nM) that binds Ras in a GTP-dependent manner.
  • the second region encodes a hydrophobic zinc finger domain, which binds Ras in a GTP- independent manner at low affinity (Kd>20 ⁇ M). This low affinity binding requires the isoprenyl group at the carboxy terminus of Ras proteins (Fig. 6).
  • Raf AAs 50-150 the high affinity Ras binding site
  • AAs50-220 the complete Ras binding site
  • the Raf fusion proteins, expressed in E. coli are convenient to express and several hundred micrograms of protein of either fragment can be purified from a liter of bacteria.
  • E. coli cells were transformed with a plasmid vector expressing the fusion protein in Fig. 6.
  • Raf fusion protein was purified by affinity chromatography on monomeric avidin- sepharose and eluted with free biotin.
  • Assay conditions were established initially with a series of titrations of Ras and Raf protein concentrations, and anti-Ras antibody dilution (Fig. 8, Panels A, B, C). The effectiveness of binding was evaluated with three parameters: i) the absolute level of AlphaScreen signal that was produced had to be above 10,000 counts per second (cps) for statistical confidence; ii) the relative Alpha signal of Ras-GTP bound to Raf had to be at least two-fold greater than Ras-GDP binding to Raf; and iii) the signal had to be depleted substantially by competition with an excess of non-biotinylated Raf protein.
  • the calculated Z' values a statistical measure of the robustness of an assay which can be used across all assay platforms, are typically between 0.7 and 0.8.
  • the Z' value for an assay is above 0.5, the assay is considered to be highly robust and reliable.
  • the Alpha signal shows a dose dependent decrease (Fig. 8, Panel D).
  • the calculated Z' value for this assay is 0.77, using the maximum inhibitory concentration of the c-Raf competitor as the basal level of expression.
  • Assays were run in the presence of 80 nM V12 K-Ras.
  • C Titration of anti-K-Ras antibody.
  • Assays were run with Ras at 160 nM and Raf at 80 nM.
  • D Inhibition of the Ras-Raf AlphaScreen Signal in the presence of competing nonbiotinylated peptide.
  • Assays were performed under optimal conditions, 160 nM Ras, 80 nM b-Raf, 1 : 1000 antibody dilution. Raf proteins were mixed prior to the addition of Ras.
  • AlphaScreen beads were used at the manufacturer's (Perkin Elmer, Inc.) recommended concentration of 20 ⁇ g/ml.
  • Fig. 9 The results of a typical 384 well plate that was part of a 10 plate screen is shown in Fig. 9.
  • This plate includes 8 inhibitor controls using the GST-c-Raf competitor polypeptide at 1 ⁇ M, three wells on each side of the plate.
  • the data in Fig. 9 is plotted as the reciprocal of the raw counts. This allows the easy visual identification of Hits as peaks that stand out in a 3- dimensional plot. If the data were to be plotted directly, the infrequent hit would be buried and nearly unnoticeable.
  • a Hit is defined in this assay as any compound that can inhibit the Ras-Raf protein-protein interaction at a level at least 50% of that incurred by the control inhibitor peptide at 1 ⁇ M. Based on this criterion, there were three Hits identified on this plate, two with high efficacy and one with partial efficacy. At least two Hits were verified upon retest. For comparison of the robustness of the high throughput screen to the original assay run by hand in triplicate, the Z value (equivalent to Z', but used when calculating noise in an actual screen with compounds present) was calculated to be 0.75.
  • GTP-Ras was mixed with biotinylated c-Raf in the presence of 20 ⁇ M concentration of each of the NCI compounds in the screen.
  • Compounds were screened for inhibition of an AlphaScreen signal at 20 ⁇ M. Compounds testing positive were rescreened in triplicate, with >90% of positives from the initial screen testing positive upon rescreen. Two assays were then performed on confirmed positives: i) the IC50 values were determined for all confirmed positives; and ii) confirmed positives were screened for nonspecific inhibition of the Alpha signal using positive control Alpha beads in which the biotin residue is conjugated directly onto the Acceptor Beads to facilitate high affinity complex formation between the Streptavidin bound Donor beads and the biotinylated Acceptor beads. Any inhibition of this strong positive control signal is evidence for nonspecific quenching by the compounds.
  • the IC50 values for quenchers in this nonspecific screen were determined. If the IC50 value of a compound for the Ras-Raf assay was at least 10-fold lower that the IC50 for nonspecific quenching, the compound would remain on the active list. Of 41 number of repeat actives, it was determined that 5 were nonspecific quenchers of the Alpha signal. The remaining 36 compounds, which showed specific inhibition in the Ras- Raf assay are listed in Table 1 below according to their potencies.
  • Compounds that have been identified as inhibitors of the Ras-Raf interaction in the cell- free high throughput screen are further characterized in one or more cell-based assays.
  • Applicants run two types of cellular assays, one that monitors the IC50 for cell proliferation and the second indicates the level of activation of the MAP kinase pathway by measuring the level of phosphorylation of MAP kinase (ERK 1 &2) and/or MAP kinase kinase (MEK), the direct Raf substrate.
  • Applicants are testing a number of cell lines for their ability undergo activation of the MAP kinase pathway under conditions of serum starvation (16 h) followed by 15 minutes of refeeding in the presence or absence of the MAP kinase kinase inhibitor compound UO126 (Fig. 10).
  • the results of this experiment indicate that in a human colon cancer cell line expressing a mutant K-Ras protein, a 15 minute pretreatment with the MAP kinase kinase inhibitor U0126 before refeeding with serum completely blocks ERK phosphorylation.
  • K-Ras oncogene bearing human colon tumor cell line HCT116 was grown in 6-well plates in the absence of serum for 16 hours followed by 15 minutes of refeeding with 10% FBS with or without a 15 minute pretreatment with the MAP kinase kinase inhibitor U0126 at 20 ⁇ M.
  • Cell extracts were prepared and parallel aliquots were loaded on two 8% polyacrylamide gels. Both gels were electroblotted to PVDF membranes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Ras et Raf sont des produits génétiques liés à divers types de cancer. On admet que l'interaction entre ces protéines est fondamentale dans leur activité. La présente invention concerne plusieurs 3,6-dihydroxy xanthènes et leurs variants oxydés servant à inhiber l'interaction entre Ras et Raf.
PCT/US2003/035418 2002-11-12 2003-11-07 Composes de xanthene destines a la chimiotherapie du cancer WO2004044219A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003291268A AU2003291268A1 (en) 2002-11-12 2003-11-07 Xanthene compounds for cancer chemotherapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US42583302P 2002-11-12 2002-11-12
US60/425,833 2002-11-12

Publications (2)

Publication Number Publication Date
WO2004044219A2 true WO2004044219A2 (fr) 2004-05-27
WO2004044219A3 WO2004044219A3 (fr) 2004-11-11

Family

ID=32313057

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/035418 WO2004044219A2 (fr) 2002-11-12 2003-11-07 Composes de xanthene destines a la chimiotherapie du cancer

Country Status (2)

Country Link
AU (1) AU2003291268A1 (fr)
WO (1) WO2004044219A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006102102A2 (fr) * 2005-03-17 2006-09-28 Marshfield Clinic Modulateurs de tgf-beta et procedes d'utilisation correspondants
WO2009124024A1 (fr) * 2008-04-01 2009-10-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions et procédés d'inhibition de la signalisation de récepteur c-met de facteur de croissance d'hépatocyte
WO2010068738A1 (fr) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mutations de mek conférant une résistance aux inhibiteurs de mek
WO2011106298A1 (fr) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Mutations de braf conférant une résistance aux inhibiteurs de braf
WO2013169858A1 (fr) 2012-05-08 2013-11-14 The Broad Institute, Inc. Méthodes de diagnostic et de traitement chez des patients ayant ou présentant un risque de développer une résistance à une thérapie anticancéreuse
WO2016148215A1 (fr) * 2015-03-17 2016-09-22 国立大学法人東京大学 INHIBITEUR DE Mint 3
WO2019108814A1 (fr) * 2017-11-29 2019-06-06 The Rockefeller University Combinaison de thérapies locales et systémiques pour l'amélioration du traitement d'affections dermatologiques
US11078540B2 (en) 2010-03-09 2021-08-03 Dana-Farber Cancer Institute, Inc. Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040033A1 (fr) * 1996-04-19 1997-10-30 Lexigen Pharmaceuticals Corp. Inhibition de la liaison de l'ige humaine a son recepteur par des composes tetracycliques pour l'attenuation de la reaction immunitaire induite par ige

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040033A1 (fr) * 1996-04-19 1997-10-30 Lexigen Pharmaceuticals Corp. Inhibition de la liaison de l'ige humaine a son recepteur par des composes tetracycliques pour l'attenuation de la reaction immunitaire induite par ige

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006102102A3 (fr) * 2005-03-17 2007-01-04 Marshfield Clinic Modulateurs de tgf-beta et procedes d'utilisation correspondants
WO2006102102A2 (fr) * 2005-03-17 2006-09-28 Marshfield Clinic Modulateurs de tgf-beta et procedes d'utilisation correspondants
US8754081B2 (en) 2008-04-01 2014-06-17 The United States of America as represented by the Secretary, Departmnet of Health and Human Services Compositions and methods for inhibition of hepatocyte growth factor receptor c-Met signaling
WO2009124024A1 (fr) * 2008-04-01 2009-10-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Compositions et procédés d'inhibition de la signalisation de récepteur c-met de facteur de croissance d'hépatocyte
US8569360B2 (en) 2008-04-01 2013-10-29 Donald P. Bottaro Compositions and methods for inhibition of hepatocyte growth factor receptor c-Met signaling
WO2010068738A1 (fr) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mutations de mek conférant une résistance aux inhibiteurs de mek
US9084781B2 (en) 2008-12-10 2015-07-21 Novartis Ag MEK mutations conferring resistance to MEK inhibitors
WO2011106298A1 (fr) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Mutations de braf conférant une résistance aux inhibiteurs de braf
US9279144B2 (en) 2010-02-25 2016-03-08 Dana-Farber Cancer Institute, Inc. Screening method for BRAF inhibitors
EP3028699A1 (fr) 2010-02-25 2016-06-08 Dana-Farber Cancer Institute, Inc. Mutations braf conférant une résistance aux inhibiteurs de braf
US11078540B2 (en) 2010-03-09 2021-08-03 Dana-Farber Cancer Institute, Inc. Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy
WO2013169858A1 (fr) 2012-05-08 2013-11-14 The Broad Institute, Inc. Méthodes de diagnostic et de traitement chez des patients ayant ou présentant un risque de développer une résistance à une thérapie anticancéreuse
WO2016148215A1 (fr) * 2015-03-17 2016-09-22 国立大学法人東京大学 INHIBITEUR DE Mint 3
JP2016172705A (ja) * 2015-03-17 2016-09-29 国立大学法人 東京大学 Ｍｉｎｔ３阻害剤
WO2019108814A1 (fr) * 2017-11-29 2019-06-06 The Rockefeller University Combinaison de thérapies locales et systémiques pour l'amélioration du traitement d'affections dermatologiques
US11426379B2 (en) 2017-11-29 2022-08-30 Provectus Pharmatech, Inc. Combination of local and systemic therapies for enhanced treatment of dermatologic conditions

Also Published As

Publication number Publication date
AU2003291268A1 (en) 2004-06-03
WO2004044219A3 (fr) 2004-11-11
AU2003291268A8 (en) 2004-06-03

Similar Documents

Publication Publication Date Title
DeClue et al. Inhibition of cell growth by lovastatin is independent of ras function
Black et al. Identification of p130Cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions
Wu et al. BRD4 phosphorylation regulates HPV E2-mediated viral transcription, origin replication, and cellular MMP-9 expression
Liu et al. Allosteric regulation of IGF2BP1 as a novel strategy for the activation of tumor immune microenvironment
AU706621B2 (en) Method and compositions for inhibiting protein kinases
Loi et al. Barrier-to-autointegration factor (BAF) involvement in prelamin A-related chromatin organization changes
US10822375B2 (en) Method for identifying a modulator of cell survival or plasticity
Sharma et al. UCS15A, a non-kinase inhibitor of Src signal transduction
WO2004044219A2 (fr) Composes de xanthene destines a la chimiotherapie du cancer
Poillet-Perez et al. GABARAPL1 tumor suppressive function is independent of its conjugation to autophagosomes in MCF-7 breast cancer cells
Shinde et al. Transcriptional reprogramming and inhibition of tumor-propagating stem-like cells by EC-8042 in ERG-positive prostate cancer
US7557085B2 (en) Metabolic-based methods for modulating gene expression
EP3497083B1 (fr) Derives heterocycliques de la naphtoquinone utilise pour le traitement du cancer incluant la maladie de cushing
US20070274912A1 (en) Histone Modifications as Binary Switches Controlling Gene Expression
US8057990B2 (en) Screening method
Morrison et al. The cellular distribution of the adenomatous polyposis coli tumour suppressor protein in neuroblastoma cells is regulated by microtubule dynamics
MX2007016542A (es) 4-anilino-3-quinolinocarbonitrilos para el tratamiento de cancer.
Oh-Hashi et al. Characterization of IRE1α in Neuro2a cells by pharmacological and CRISPR/Cas9 approaches
Zhao et al. Interaction of positive coactivator 4 with histone 3.3 protein is essential for transcriptional activation of the luteinizing hormone receptor gene
KR101871593B1 (ko) HIF-1α의 메틸화를 표적으로 하는 혈관신생억제제 스크리닝 방법
US7214771B2 (en) Nucleic acid and protein expression thereby and their involvement in stress
CA2477590A1 (fr) Inhibiteurs de sumo
WO2008125836A2 (fr) Procédés et utilisations
KR102626102B1 (ko) N-데그론 경로의 n-말단 아르기닐화에 의한 펙소파지의 조절, pbd 의 예방, 개선 또는 치료하는 물질의 스크리닝 방법, pbd를 진단하는 방법 및 펙소파지 조절, 또는 pbd 의 예방, 개선 또는 치료용 조성물
Lata et al. HDAC inhibitors rescue MeCP2T158M speckles in a high content screen

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP