WO2006078886A2 - Composes et compositions utilises comme modulateurs de la voie de signalisation wnt - Google Patents

Composes et compositions utilises comme modulateurs de la voie de signalisation wnt Download PDF

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WO2006078886A2
WO2006078886A2 PCT/US2006/002007 US2006002007W WO2006078886A2 WO 2006078886 A2 WO2006078886 A2 WO 2006078886A2 US 2006002007 W US2006002007 W US 2006002007W WO 2006078886 A2 WO2006078886 A2 WO 2006078886A2
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compound
wnt
compounds
wnt signaling
wnt signal
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PCT/US2006/002007
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WO2006078886A3 (fr
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Sheng Ding
Jun Liu
Peter G. Schultz
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Irm Llc
The Scripps Research Institute
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Publication of WO2006078886A3 publication Critical patent/WO2006078886A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention provides a novel class of compounds and methods of using such compounds to study the activity of the Wnt signaling pathway.
  • the Wnt signaling pathway plays a role in a variety of biological processes by regulating genes involved in cellular adhesion, proliferation and differentiation.
  • the Wnt ligand activates downstream signal transduction through interaction with receptors of the 'Frizzled' family on the cell surface.
  • This interaction through several cytoplasmic relay components, leads to inhibition of ⁇ -catenin phosphorylation by the Axin, APC and GSK-3 ⁇ complex, and results in accumulation of ⁇ -catenin in the cytoplasm, ⁇ - catenin then translocates into the nucleus, forms a complex with T cell factor/lymphoid enhancer factor (TCF/LEF) which drives target gene expression.
  • TCF/LEF T cell factor/lymphoid enhancer factor
  • the present invention provides compounds of Formula I:
  • n is selected from 1 , 2 and 3 ;
  • Ri is selected from hydrogen and Ci- ⁇ alkoxy
  • R 2 , R 3 and R 4 are independently selected from hydrogen and C ⁇ aUcyl
  • R 5 is selected from C 6 -i 2 aryl-Co 4 alkyl and wherein any aryl or heteroaryl of R 5 is optionally substituted with 1 to 3 radicals independently selected from hydroxy, cyano and halo; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method for modulating the Wnt signaling pathway.
  • Compounds of the invention that modulate the Wnt signaling pathway are useful tools for studying biological processes that involve Wnt signaling such as hematopoietic stem cell renewal, mesenchymal progenitor cell differentiations, embryonic limb development, and the like.
  • Wnt signaling such as hematopoietic stem cell renewal, mesenchymal progenitor cell differentiations, embryonic limb development, and the like.
  • compounds of the invention can be useful for studying, for example, embryogenesis and adult tissue homeostasis and regeneration.
  • compounds of the invention can be used to reveal new physiological effects of Wnt signaling in model organisms and can be used to develop new therapeutic targets.
  • the present invention provides a method of treating a disease in an animal in which modulation of the Wnt signaling pathway activity, can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • Formula I in the manufacture of a medicament for treating a disease in an animal in which aberrant Wnt signaling pathway activity contributes to the pathology and/or symptomology of the disease.
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched.
  • Ci_ 4 -alkoxy includes, methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • An "Agonist”, as used herein, refers to a compound of the invention that mimics or upregulates (e. g. potentiates or supplements) a Wnt-signaling bioactivity.
  • An agonist therapeutic can be a compound that upregulates expression of a member of the Wnt-signaling pathway such as the beta-catenin gene or which increases at least one bioactivity of the beta- catenin protein.
  • An agonist can also be a compound which increases the interaction of a beta-catenin polypeptide with another molecule, e. g, a member of the TCF- 4/LEF family.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl may be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl above where one or more of the ring members is a heteroatom.
  • heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3- iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3-8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.
  • "Halogen" (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • Wnt pathway and Wnt signaling pathway refer to the pathway by which binding of the Wnt protein to its extracellular receptor is translated into the nucleus and results in transcriptional activation of a variety of genes.
  • the Wnt signaling pathway involves a variety of proteins including Frizzled, Disheveled, Axin, APC, GSK-3 beta, beta- catenin, LEF/TCF transcription factors, etc. Cells from many different species express homologs of the proteins involved in the Wnt signaling pathway and accordingly have functionally equivalent Wnt signaling pathways.
  • Ri is selected from hydrogen and methoxy
  • R 2 , R 3 and R 4 are hydrogen
  • R 5 is selected from benzo[l,3]dioxol-5-yl and benzyl optionally substituted with hydroxy.
  • Preferred compounds include: N 4 -benzo[l,3]dioxol-5-ylmethyl-6-(3- methoxy-phenyl)-pyrimidine-2,4-diamine; 4-[2-(2-amino-6-phenyl-pyrimidin-4-ylamino)- ethyl]-phenol; N 4 -benzo[l,3]dioxol-5-ylmethyl-6-phenyl-pyrimidine-2,4-diamine; and 4- ⁇ 2- [2-amino-6-(3-methoxy-phenyl)-pyrimidin-4-ylamino]-ethyl ⁇ -phenol.
  • Compounds of the invention are further detailed in the Examples and Table I, infra.
  • the invention provides for a method for modulating Wnt signal transduction comprising contacting a cell with an amount of a compound of claim 1, effective to change Wnt signal transduction.
  • the method involves modulating ⁇ -catenin and TCF mediated transcriptional control and may or may not include stimulating the activity of GSK-3 ⁇ . Preferred methods are exemplified in the Assays, infra.
  • modulating the Wnt signal transduction results in mimicking Wnt signaling bioactivity.
  • the Wnt signal transduction results in upregulating the Wnt signaling bioactivity.
  • compounds of the invention can be used to modulate the Wnt signal pathway and thereby can be useful for studying biological processes that involve Wnt signaling, such as stem cell renewal, mesenchymal progenitor cell differentiation, embryonic limb development and the like.
  • the Wnt gene family encodes secreted ligand proteins that serve key roles in differentiation and development. This family comprises at least 15 vertebrate and invertebrate genes including the Drosophila segment polarity gene wingless and one of its vertebrate homologues, integrated from which the Wnt name derives. The Wnt proteins, via their signal transduction components and links to the hedgehog development pathway, appear to facilitate a number of developmental and homeostatic processes. [0027] ⁇ -catenin protein transduces the Wnt signal from the cytoplasm to the nucleus.
  • ⁇ -catenin In the absence of Wnt signaling, ⁇ -catenin is constitutively degraded by the proteasome and can be found in a multimeric complex with conductin (or axin), APC (Adenomatous Polyposis CoIi) and GSK-3 ⁇ .
  • GSK-3 ⁇ a serine/threonine kinase, phosphorylates ⁇ -catenin thus stimulating its degradation by the proteasome.
  • the GSK-3 ⁇ kinase Upon Wnt signaling, the GSK-3 ⁇ kinase is inactivated leading to stabilization of the ⁇ -catenin protein, ⁇ -catenin is then released from the multimeric complex and translocates into the nucleus. [0028] Once in the nucleus, ⁇ -catenin interacts with the LEF/TCF (Lymphoid
  • Enhancer Factor/T-Cell Factor family of HMG (High Mobility Group) box transcription factors.
  • the LEF/TCF factors are stimulated through interaction with ⁇ -catenin to become potent transactivators of a number of genes including c-myc, cyclin Dl, c-jun and hedgehog
  • the invention provides for an agonist therapeutic, which can mimic or potentiate the activity of the Wnt-signaling pathway by, for example, promoting, mimicking, or potentiating the interaction between ⁇ -catenin and a member of the TCF/LEF family.
  • An agonist therapeutic of the invention has utility for disorders of cell fate and can be administered: (1) in diseases or disorders involving an absence or decreased (relative to normal, or desired) levels of Wnt function, for example, in patients where any member of the Wnt-signaling pathway is lacking, genetically defective, biologically inactive or underactive, or under expressed; and (2) in diseases or disorders wherein in vitro (or in vivo) assays indicate the utility of Wnt agonist administration.
  • An agonist therapeutic is administered (1) in diseases or disorders involving an absence or decreased levels of Wnt function, for example, inpatients where ⁇ - catenin is lacking, genetically defective, biologically inactive or underactive, or under expressed; and (2) in diseases or disorders wherein in vitro (or in vivo) assays indicate the utility of Wnt agonist administration.
  • Absence of Wnt pathway function can be readily detected, e. g., by obtaining a patient tissue sample (e. g., from biopsy tissue) and assaying it in vitro for protein levels, structure and/or activity of the expressed ⁇ -catenin protein.
  • In vitro assays which can be used to determine whether administration of a specific agonist therapeutic is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a therapeutic, and the effect of such a therapeutic upon the tissue sample is observed.
  • Compounds of the invention can be used as therapeutics for the promotion of cell growth, upon a patient cell sample from tissue having or suspected of having a hypo- proliferative disorder, such as disorders including diseases or conditions associated with insufficient cell proliferation, such as stimulation of tissue repair, tissue regeneration, wound healing, neovascularization, and the like.
  • a hypo- proliferative disorder such as disorders including diseases or conditions associated with insufficient cell proliferation, such as stimulation of tissue repair, tissue regeneration, wound healing, neovascularization, and the like.
  • the present invention further provides useful tools for the study of the Wnt signal pathway and/or for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositioiis", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositioiis", infra
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of Formula I and a co-agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted' participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic
  • n, Ri, R 2 , R 3 , R 4 and R 5 are as described in the Summary of the
  • a compound of Formula I is formed by reacting a compound of formula 2 and formula 3 in the presence of a suitable solvent (for example, water, acetonitrile, or the like) and in the presence of a suitable catalyst (for example, Pd(PPh 3 ) 4 , or the like).
  • a suitable solvent for example, water, acetonitrile, or the like
  • a suitable catalyst for example, Pd(PPh 3 ) 4 , or the like.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para- nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Hydrates of compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of Formula I can be made by a process, which involves:
  • ⁇ -catenin/TCF transcriptional activity is dependent on Wnt signaling and can be used to monitor activity of the Wnt signaling pathway.
  • a reporter based cellular assay is used to measure the transcriptional activity of ⁇ -catenin/TCF in 384-well cell culture plates.
  • the reporter construct encodes the luciferase gene driven by ⁇ -catenin/TCF responsive elements.
  • 293T cells are transiently transfected with the reporter construct in T75 cell culture flasks and replated into 384-well cell culture plates after overnight culture. After 24 hours, cells are treated with lO ⁇ M of a compound of the invention and incubated for a further 24 hours.
  • Compounds of Formula I preferably have an EC50 of less than or equal to l ⁇ M.
  • N 4 -benzo[l ,31dioxol-5-ylmemyl-6-f3-methoxy-phenyiypyrimidine-2,4- diamine induces ⁇ -catenin and TCF dependent transcriptional activity in a dose dependent manner with an EC 50 of 0.7 ⁇ M.
  • Compounds 2, 3 and 4 of table 1 have an EC 50 of l.O ⁇ M, 0.9 ⁇ M and 0.8 ⁇ M, respectively.
  • the Wnt signal is transduced through its receptor, resulting in formation of a heterodimeric complex of ⁇ -catenin and TCF, which drives down stream target expression.
  • a dominant negative TCF4 was constructed and transfected into cells in the absence/presence of compounds of the invention.
  • the dominant negative TCF4 contains a DNA binding domain but lacks the ⁇ -catenin interaction motif, leading to sequestration of TCF factor binding sites and subsequent blocking of ⁇ -catenin and TCF dependent transcriptional activity.
  • the gene encoding the dominant negative TCF4 is generated by PCR and cloned into an eukaryotic expression vector pcDNA3.
  • Dominant negative TCF4 is co-transfected with the Wnt-responsive reporter construct into 293T cells, and 16-24 hours later the compounds (agonists) are added to cells at the final concentration of 1-10 ⁇ M. After another 24 hours, luciferase activity is measured and EC5 0 S are calculated when the signal is activated by 50%.
  • Compounds of the invention show substantial head defects ranging from significantly diminished heads and complete loss of eyes to reduced eyes and heads while the posterior structures of tadpoles remained intact. This phenotype is consistent with Wnt overexpression in head specification during early embryonic development suggesting that the compounds of the invention mimic the effects of Wnt at the whole organism level.

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Abstract

L'invention concerne une nouvelle classe de composés et des méthodes d'utilisation de ces composés pour étudier l'activité de la voie de signalisation Wnt.
PCT/US2006/002007 2005-01-18 2006-01-18 Composes et compositions utilises comme modulateurs de la voie de signalisation wnt WO2006078886A2 (fr)

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WO2009026319A1 (fr) * 2007-08-20 2009-02-26 Wyeth Analogues de naphtylpyrimidine, naphtylpyrazine et naphtylpyridazine et leur utilisation comme agonistes du système de communication cellulaire wnt-bêta-caténine
US8551782B2 (en) 2006-03-24 2013-10-08 Children's Medical Center Corporation Methods for promoting HSC engraftment
US9051548B2 (en) 2009-02-03 2015-06-09 Children's Medical Center Corporation Methods for enhancing hematopoietic stem/progenitor cell engraftment
US9056085B2 (en) 2009-02-03 2015-06-16 Children's Medical Center Corporation Methods for enhancing hematopoietic stem/progenitor cell engraftment
CN105143206A (zh) * 2012-11-27 2015-12-09 托马斯·黑勒戴药物研究基金会 用于治疗癌症的嘧啶-2,4-二胺衍生物
AU2013213727B2 (en) * 2006-10-20 2016-03-17 Children's Medical Center Corporation Method to enhance tissue regeneration
WO2016097035A1 (fr) * 2014-12-18 2016-06-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Protéines de la voie de signalisation wnt et leurs utilisations dans le diagnostic et le traitement de troubles de l'hypopigmentation
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US20180125781A1 (en) * 2009-10-21 2018-05-10 Otonomy, Inc. Modulation of gel temperature of poloxamer-containing formulations
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