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WO2011094749A2 - Inhibiteurs à petites molécules qui bloquent l'assemblage du complexe de signalisation de tgf-bêta - Google Patents

Inhibiteurs à petites molécules qui bloquent l'assemblage du complexe de signalisation de tgf-bêta Download PDF

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WO2011094749A2
WO2011094749A2 PCT/US2011/023380 US2011023380W WO2011094749A2 WO 2011094749 A2 WO2011094749 A2 WO 2011094749A2 US 2011023380 W US2011023380 W US 2011023380W WO 2011094749 A2 WO2011094749 A2 WO 2011094749A2
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tgf
aryl
phenyl
alkyl
inhibitors
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PCT/US2011/023380
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WO2011094749A3 (fr
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Andrew Hinck
Luzhe Sun
York Tomita
Yumi Ueda
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Board Of Regents, The University Of Texas System
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the invention generally relates to compounds for the treatment of fibrotic disorders and cancer. More particularly, the invention relates to the treatment of fibrotic disorders and cancer using inhibitors of the TGF- ⁇ signaling complex.
  • TGF- ⁇ isoforms are vertebrate signaling ligands that coordinate wound repair, suppress the immune system, and regulate the growth and differentiation of epithelial cells.
  • TGF ⁇ s as well as other ligands of the TGF- ⁇ superfamily, such as Activins, Bone Morphogenetic Proteins (BMPs), and Growth and Differentiation Factors (GDFs), signal by binding and bringing together two single-pass transmembrane receptor kinases, known as RI and RII. This triggers a phosphorylation cascade, wherein RII phosphorylates RI, leading to its activation, and the subsequent phosphorylation of cytoplasmic effectors, a major one of which are the Smads.
  • RIs and five RIIs have been identified in humans. Specificities have been determined based on cell-based affinity labeling studies with radiolabeled ligands and have enabled the identification of major ligands for most receptors of the superfamily, including those specific for TGF-ps, Activins, BMPs, and GDFs. Such studies suggest that there appear to be two fundamental mechanisms of assembly, the interdependent one exemplified by TGF ⁇ s and Activins and the independent one exemplified by BMPs and GDFs.
  • TGF- ⁇ isoforms play prominent roles in human disease, especially cancer.
  • the loss of the tumor suppressive activity of TGF- ⁇ by mutational inactivation of the protein components of the TGF- ⁇ pathway leads to certain hereditary forms of colon and pancreatic cancer.
  • These types of defects are relatively rare and in most human cancers, including those of the breast, the TGF- ⁇ pathway typically remains intact. This usually has adverse consequences, as many cancer cells over express c-myc, which antagonizes TGF- ⁇ ability to inhibit cell growth.
  • the tumor promoting activities of TGF- ⁇ including its ability to function as a potent suppressor of the immune system, induce endothelial-tomesenchymal transitions, and promote angiogenesis, remain intact.
  • TGF- ⁇ has also been has been demonstrated to play an important role in the metastasis of breast cancer cells to the lungs and to bone, the leading cause of morbidity and mortality in patients with advanced breast cancer.
  • TGF- ⁇ is thought to drive a "vicious" cycle, whereby the breast cancer cells release osteolytic and pro-angiogenic factors, such IL11 and OPN and CTGF and FGF5, respectively.
  • TGF- ⁇ which is stored in bone, is released and acts on the cancer cells to induce pro-metastatic factors, such as CTGF and IL11 through the Smad pathway.
  • pro-metastatic factors such as CTGF and IL11
  • high level TGF- ⁇ expression has been shown to potently suppress immune surveillance, promoting tumor growth and metastasis.
  • antisense oligonucleotides that repress the expression of TGF ⁇ 2 have proven to have significant efficacy in prolonging survival rates in patients with recurrent high-grade glioma and anaplastic astrocytoma.
  • TGF- ⁇ tissue fibrosis.
  • TGF ⁇ 's role in fibrosis of organs such as the kidney and lung has been ascribed to the coordinate effect that TGF- ⁇ has in promoting the accumulation of protein components of the extracellular matrix, such as collagen and fibronectin.
  • TGF-p's role as a tumor-promoter and as a promoter of fibrosis had been clearly established, it was less clear whether TGF- ⁇ could be safely inhibited due to its established role as a tumor suppressor.
  • a transgenic mouse that expressed a soluble form of the TGF- ⁇ type II receptor (sRII) at high levels has been studied. The results showed that sRII expressing mice, an established TGF- ⁇ antagonist, rendered the mice no more prone to tumorigenesis than normal mice. The mice were also found to be much less prone to undergo metastasis in an MMTV-neu model of metastatic breast cancer.
  • TGF- ⁇ A number of strategies have been proposed for inhibiting TGF- ⁇ , including TGF- ⁇ monoclonal antibodies, soluble forms of the TGF- ⁇ receptors, TGF- ⁇ antisense oligonucleotides, and small molecules that target the ATP binding site of the ⁇ kinase.
  • TGF- ⁇ monoclonal antibodies soluble forms of the TGF- ⁇ receptors
  • TGF- ⁇ antisense oligonucleotides small molecules that target the ATP binding site of the ⁇ kinase.
  • specificities are either too limited, such as the ⁇ ⁇ kinase inhibitors, which target a number of other related kinases, including the TGF- ⁇ superfamily type I receptor, ActRIb, or too narrow, such as the soluble TGF- ⁇ type III receptor that targets predominantly TGF-P2, but not TGF ⁇ s 1 and 3, or the soluble TGF- ⁇ type II receptor that targets predominantly TGF-Ps 1 and 3, but not TGF-P2.
  • a method of treating fibrotic disorders or cancer in a subject comprises administering to a subject who would benefit from such treatment a therapeutically effective amount of one or more TGF- ⁇ inhibitors.
  • the TGF- ⁇ inhibitor has the structure:
  • each R is, independently, H, -OR 1 , -NR ⁇ 2 , -SO3R 1 , -NC(0)-R 3 , -OC(0)-R 3 ,
  • N CR 1 R 2 , at least one R being -S0 3 R ! ; where each R 1 is, independently, H, alkyl, phenyl, or aryl;
  • R 2 is H, alkyl, phenyl, or aryl
  • R 3 is alkyl, phenyl, aryl, or an amino-acid residue.
  • the TGF- ⁇ inhibitor has the structure:
  • each R 1 is, independently, H, alkyl, phenyl, or aryl;
  • R 2 is H, alkyl, phenyl, or aryl
  • R 3 is alkyl, phenyl, aryl, or an amino-acid residue.
  • a phamiaceutical composition for treating fibrotic disorders or cancer in a subject comprises one or more TGF- ⁇ inhibitors and a pharmaceutically acceptable carrier.
  • a method of screening for compounds that inhibit assembly of the TGF- ⁇ ternary complex includes measuring the degree of polarization exhibited by fluorescently- tagged TfiRl extracellular domain as its binds to T ⁇ RII:TGF- ⁇ 3 complex in the presence of one or more compounds. The measured change in the degree of polarization may be used to determine the inhibitory effect of the one or more compounds.
  • FIG. 1 depicts graphical data from a rapid fluorescence polarization (FP) assay used to screen for compounds that inhibit assembly of the TGF- ⁇ ternary complex;
  • FP rapid fluorescence polarization
  • FIG. 2 depicts fluorescence polarization (FP) assay results monitored when a ternary complex of TGF- ⁇ is formed or it is reversed by the novel TGF- ⁇ inhibitors;
  • FIGS. 3A-3C depict the results of SPR experiments to detect direct binding of TGF- ⁇ inhibitors to immobilized ⁇ ;
  • FIGS. 4A-4C depicts the results of the effect of TGF- ⁇ inhibitors on binding of ⁇ to TGF ⁇ 3 in the presence of a saturating concentration of ⁇ (4 ⁇ );
  • FIG. 5 depicts data collected from Cell-based Smad phosphorylation assays to evaluate the biological activity of the novel TGF- ⁇ inhibitors.
  • administering when used in the context of providing a pharmaceutical or nutraceutical composition to a subject generally refers to providing to the subject one or more pharmaceutical, “over-the-counter” (OTC) or
  • nutraceutical compositions in combination with an appropriate delivery vehicle by any means such that the administered compound achieves one or more of the intended biological effects for which the compound was administered.
  • a composition may be administered by parenteral, subcutaneous, intravenous, intracoronary, rectal, intramuscular, intra- peritoneal, transdermal, or buccal routes of delivery.
  • parenteral subcutaneous, intravenous, intracoronary, rectal, intramuscular, intra- peritoneal, transdermal, or buccal routes of delivery.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, weight, and/or disease state of the recipient, kind of concurrent treatment, if any, frequency of treatment, and/or the nature of the effect desired.
  • the dosage of pharmacologically active compound that is administered will be dependent upon multiple factors, such as the age, health, weight, and/or disease state of the recipient, concurrent treatments, if any, the frequency of treatment, and/or the nature and magnitude of the biological effect that is desired.
  • phrases such as "pharmaceutical composition,” “pharmaceutical formulation,” “pharmaceutical preparation,” or the like generally refer to formulations that are adapted to deliver a prescribed dosage of one or more pharmacologically active compounds to a cell, a group of cells, an organ or tissue, an animal or a human. Methods of incorporating pharmacologically active compounds into pharmaceutical preparations are widely known in the art. The determination of an appropriate prescribed dosage of a pharmacologically active compound to include in a pharmaceutical composition in order to achieve a desired biological outcome is within the skill level of an ordinary practitioner of the art.
  • a pharmaceutical composition may be provided as sustained-release or timed-release formulations.
  • Such formulations may release a bolus of a compound from the formulation at a desired time, or may ensure a relatively constant amount of the compound present in the dosage is released over a given period of time.
  • Terms such as “sustained release” or “timed release” and the like are widely used in the pharmaceutical arts and are readily understood by a practitioner of ordinary skill in the art.
  • Pharmaceutical preparations may be prepared as solids, semi-solids, gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols, powders, or combinations thereof.
  • compositions, formulations and preparations may include pharmaceutically acceptable salts of compounds. It will further be appreciated by an ordinary practitioner of the art that the term also encompasses those pharmaceutical compositions that contain an admixture of two or more pharmacologically active compounds, such compounds being administered, for example, as a combination therapy.
  • salts includes salts prepared from by reacting pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases, with inorganic or organic acids.
  • Pharmaceutically acceptable salts may include salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, etc. Examples include the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '- dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • reducing when used in the context of modulating a pathological or disease state, generally refers to the prevention and/or reduction of at least a portion of the negative consequences of the disease state.
  • the term(s) when used in the context of an adverse side effect associated with the administration of a drug to a subject, generally refer to a net reduction in the severity or seriousness of said adverse side effects.
  • subject generally refers to a mammal, and in particular to a human.
  • treat generally refers to an action taken by a caregiver that involves substantially inhibiting, slowing or reversing the progression of a disease, disorder or condition, substantially ameliorating clinical symptoms of a disease disorder or condition, or substantially preventing the appearance of clinical symptoms of a disease, disorder or condition.
  • terapéuticaally effective amount is meant an amount of a drug or pharmaceutical composition that will elicit at least one desired biological or physiological response of a cell, a tissue, a system, animal or human that is being sought by a researcher, veterinarian, physician or other caregiver.
  • structure-based inhibitors that interfere with assembly of the TGF- ⁇ signaling complex have been developed.
  • This approach for inhibiting TGF- ⁇ has only recently become feasible based on the structure the TGF- ⁇ signaling complex (TGF ⁇ 3 bound to the extracellular domains of ⁇ and ⁇ ), which we have recently determined.
  • TGF ⁇ 3 bound to the extracellular domains of ⁇ and ⁇ which we have recently determined.
  • these assembly inhibitors are highly specific and as such have a major advantage over TGF- ⁇ kinase inhibitors, the only other class of small molecules known to target TGF- ⁇ .
  • the underlying reason for the expected high specificity relates to the distinct manner by which TGF- ⁇ has been shown to assemble its signaling complex.
  • TGF- ⁇ assemble its signaling complex in a distinct manner relative to that of other grown factors that effect tumor cell growth, but also from that of other members of the TGF- ⁇ superfamily.
  • the compounds we have identified have excellent bioavailability since they are small and designed to function extracellularly. This represents an important advantage compared to both the macromolecular ligand traps that function extracellularly, but which diffuse slowly, as well as the kinase inhibitors, which act intracellularly.
  • TGF- ⁇ isoforms not just one or two, such as the antisense oligos or soluble type II receptor, which preferentially binds and antagonizes TGF- ⁇ and TGF ⁇ 3, but not TGF ⁇ 2, or the soluble type III receptor, which preferentially binds and antagonizes TGF ⁇ 2, but not TGF- ⁇ and TGF- ⁇ 3.
  • the antisense oligos or soluble type II receptor which preferentially binds and antagonizes TGF- ⁇ and TGF ⁇ 3, but not TGF ⁇ 2, or the soluble type III receptor, which preferentially binds and antagonizes TGF ⁇ 2, but not TGF- ⁇ and TGF- ⁇ 3.
  • TGF- ⁇ inhibitors include compounds having the general structure (I):
  • each R 1 is, independently, H, alkyl, phenyl, or aryl;
  • R 2 is H, alkyl, phenyl, or aryl
  • R 3 is alkyl, phenyl, aryl, or an amino-acid residue.
  • amino-acid residue refers to the side chain of an amino acid. Natural and unnatural side chains may be present. Examples of side chains of amino acids include, but are not limited to, H (glycine); -CH 3 (alanine); -CH(C]3 ⁇ 4)-CH 3 (valine); -CH 2 - CH(CH 3 )-C3 ⁇ 4 (leucine); -CH(CH 3 )-CH 2 -CH 3 (isoleucine); -CH 2 -Ph (phenylalanine); -CH 2 -C3 ⁇ 4- S-CH 3 (methionine); -CH 2 -OH (serine); -CH(CH 3 )-OH (threonine); -CH 2 -SH (cysteine); -CH 2 - Ph-OH (tyrosine); -CH 2 -C(0)-NH 2 (aspargine); -CH 2 -CH 2 -C(0)-NH 2 (glutamine); -CH 2
  • a compound of structure (I) is a pharmaceutically acceptable salt.
  • the compound of structure (I) is a sodium salt.
  • TGF- ⁇ inhibitors include compounds having the general structure
  • R is -OR 1 or -NR ! R 2 ;
  • each R 1 is, independently, H, alkyl, phenyl, or aryl
  • R 2 is H, alkyl, phenyl, or aryl.
  • TGF- ⁇ inhibitors include compounds having the general structure (IB):
  • R is -OR 1 or -NR*R 2 ;
  • each R 1 is, independently, H, alkyl, phenyl, or aryl
  • R 2 is H, alkyl, phenyl, or aryl.
  • the compound of structure I is not NSC37176.
  • TGF- ⁇ inhibitors include compounds having the general structure (IV):
  • each R 1 is, independently, H, alkyl, phenyl, or aryl;
  • R 2 is H, alkyl, phenyl, or aryl
  • R 3 is alkyl, phenyl, aryl, or an amino-acid residue.
  • a compound of structure (IV) is a pharmaceutically acceptable salt.
  • TGF- ⁇ inhibitors include compounds having the general structure (IV):
  • L 2 is -NH-, -C(O)-, or -0-;
  • each R is, independently, -OR 1 , or -NR R 2 ;
  • each R 1 is, independently, H, alkyl, phenyl, or aryl
  • R 2 is H, alkyl, phenyl, or aryl
  • a specific example of a compound having general structure (IV) is NSC 115372 (V).
  • a method of treating fibrotic disorders or cancer in a subject includes administering to a subject who would benefit from such treatment a therapeutically effective amount of one or more TGF- ⁇ inhibitors.
  • One or more TGF- ⁇ inhibitors, as described in Formulas (I) - (V) may be used to treat fibrotic disorders or cancer in a subject.
  • one or more TGF- ⁇ inhibitors e.g., any of the compounds of Formulas (I) - (V) may be formulated in a pharmaceutical composition.
  • any suitable route of administration may be employed for providing a subject with an effective dosage of the TGF- ⁇ inhibitors described herein.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions may include those compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy .
  • compositions may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • the pharmaceutical preparations may be manufactured in a manner which is itself known to one skilled in the art, for example, by means of conventional mixing, granulating, dragee- making, softgel encapsulation, dissolving, extracting, or lyophilizing processes.
  • pharmaceutical preparations for oral use may be obtained by combining the compositions with solid and semi-solid excipients and suitable preservatives, and/or co-antioxidants.
  • the resulting mixture may be ground and processed.
  • the resulting mixture of granules may be used, after adding suitable auxiliaries, if desired or necessary, to obtain tablets, softgels, lozenges, capsules, or dragee cores.
  • Suitable excipients may be fillers such as saccharides (e.g., lactose, sucrose, or mannose), sugar alcohols (e.g., mannitol or sorbitol), cellulose preparations and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate).
  • binders may be used such as starch paste (e.g., maize or corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone).
  • Disintegrating agents may be added (e.g., the above-mentioned starches) as well as carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate).
  • Auxiliaries are, above all, flow-regulating agents and lubricants (e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or PEG).
  • Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices.
  • Soft gelatin capsules are provided with suitable coatings, which, typically, contain gelatin and/or suitable edible dye(s).
  • Animal component- free and kosher gelatin capsules may be particularly suitable for the embodiments described herein for wide availability of usage and consumption.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol (PEG) and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, including dimethylsulfoxide (DMSO),
  • tetrahydrofuran THF
  • acetone acetone
  • ethanol etrahydrofuran
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate
  • Dye stuffs or pigments may be added to the tablets or dragee coatings or soft gelatin capsules, for example, for identification or in order to characterize combinations of active compound doses, or to disguise the capsule contents for usage in clinical or other studies.
  • TGF- ⁇ inhibitors will typically be formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml.
  • the appropriate dosage of the composition will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the compositions are administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the composition, and the discretion of the attending physician.
  • the composition is suitably administered to the patient at one time or over a series of treatments.
  • TGF- ⁇ inhibitor is an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful.
  • the effectiveness of the composition in preventing or treating disease may be improved by administering the composition serially or in combination with another agent that is effective for those purposes, such as another anti-cancer agent.
  • another agent that is effective for those purposes, such as another anti-cancer agent.
  • Such other agents may be present in the composition being administered or may be administered separately.
  • the composition may be suitably administered serially or in
  • a method of screening for compounds that inhibit assembly of the TGF- ⁇ ternary complex includes:
  • TGF- ⁇ 1 , TGF ⁇ 2, or TGF-p3 TGF- ⁇ 1 , TGF ⁇ 2, or TGF-p3
  • a dimeric form of the ⁇ - ⁇ extracellular domain such as Fc- ⁇
  • a dimeric form of the ⁇ - ⁇ extracellular domain such as Fc- ⁇
  • a dimeric form of the ⁇ - ⁇ extracellular domain such as Fc- ⁇
  • a dimeric form of the ⁇ - ⁇ extracellular domain such as Fc- ⁇ , is used in the method of screening compounds that inhibit assembly of the TGF- ⁇ ternary complex.
  • Novel "assembly" inhibitor leads were initially determined using computer-based target site analysis of the TGF- ⁇ receptor complex coupled with computer-based virtual screening of the National Cancer Institute Developmental Therapeutics Program (NCI-DTP) repository.
  • NCI-DTP National Cancer Institute Developmental Therapeutics Program
  • the pocket was characterized as having the following properties: it is large and deep enough to accommodate drug-like molecules; it is located on the surface of one of the receptors (e.g., ⁇ ), and hence once filled with an inhibitor should equally block complex assembly and signaling by all three TGF- ⁇ isoforms; and it is involved in crucial interactions required for complex assembly; in particular it functions as the acceptor pocket for V22 and F24 from the N- terminal tail of the ⁇ .
  • ⁇ the receptors
  • the freely available 140,000 NCI-DTP library was scanned using the program AUTODOCK4.
  • the inhibitory activities of the 40 top-ranked compounds selected by virtual screening were assessed using a fluorescent polarization (FP) assay developed specifically for this purpose.
  • FP fluorescent polarization
  • the principle of this assay is that the degree of polarization exhibited by fiuorescently- tagged ⁇ extracellular domain (11 kDa) will increase as its binds to the ⁇ : ⁇ - ⁇ 3 complex (58 kDa) and that this increase will be specifically blocked by small molecules that bind into the critical pocket on the surface of ⁇ .
  • the flourophore was attached on lysine residues using a commercially available succinimidyl ester-Alexa488 conjugate, which is ideal as the structure of the TGF- ⁇ ternary complex showed that there are no lysine residues in ⁇ binding interface with either TGF- ⁇ or ⁇ .
  • the polarization of fluorescently labeled ⁇ was shown to increase as the concentration of added ⁇ : ⁇ - ⁇ binary complex increases and that this increase can be reversed by the addition of unlabeled ⁇ .
  • FIG. 1 Data generated from a rapid fluorescence polarization (FP) assay used to screen for compounds that inhibit assembly of the TGF- ⁇ ternary complex is shown in FIG. 1. As shown in the left panel, the polarization of Alexa488 labeled ⁇ increases as the concentration of the ⁇ - ⁇ binary complex is increased. This increase can be reversed by a competitor, such as unlabeled ⁇ as shown in the right panel.
  • FP rapid fluorescence polarization
  • TPRJI:TGF-P3 binary complex (0.5 ⁇ ) in the presence of increasing concentrations of inhibitor.
  • the results showed that the TpRJI:TGF- 3 binary complex yielded a readily detectable response and that this was inhibited by approximately 30% and over 95% of its maximum value when NSC 11372 was included at concentrations of 1 and 10 ⁇ , respectively (FIG. 3).
  • a control injection was performed in which the binary complex was injected in the presence of DMSO.
  • the sensorgram from this control was coincident with the sensorgram when the binary complex alone was injected, showing that the decrease was not caused by the DMSO.
  • Smad2 and Smad3 are the cytoplasmic mediators of the TGF- ⁇ signaling pathway and are phosphorylated directly by the TGF- ⁇ receptors after the ligand binds to them and assembles them into a signaling complex.
  • Smad2 and Smad3 are the cytoplasmic mediators of the TGF- ⁇ signaling pathway and are phosphorylated directly by the TGF- ⁇ receptors after the ligand binds to them and assembles them into a signaling complex.

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Abstract

L'invention porte sur un procédé de traitement de troubles fibrotiques ou du cancer dans un sujet, qui comprend l'administration à un sujet pour lequel un tel traitement serait bénéfique d'une quantité thérapeutiquement efficace d'un ou plusieurs inhibiteurs de TGF-β. L'invention porte également sur des procédés de criblage pour des composés qui inhibent l'assemblage du complexe ternaire de TGF-β.
PCT/US2011/023380 2010-02-01 2011-02-01 Inhibiteurs à petites molécules qui bloquent l'assemblage du complexe de signalisation de tgf-bêta WO2011094749A2 (fr)

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US30022410P 2010-02-01 2010-02-01
US61/300,224 2010-02-01

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WO2011094749A2 true WO2011094749A2 (fr) 2011-08-04
WO2011094749A3 WO2011094749A3 (fr) 2011-12-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018094173A1 (fr) * 2016-11-18 2018-05-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Monomères de tgf-bêta modifiés et leur utilisation pour inhiber la signalisation de tgf-bêta

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US6670387B1 (en) * 1998-12-17 2003-12-30 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2004076640A2 (fr) * 2003-02-25 2004-09-10 Ambion, Inc. Inhibiteurs d'angiogenine et de rnases a petites molecules et leurs procedes d'utilisation in vivo et in vitro
WO2009035430A2 (fr) * 2006-11-14 2009-03-19 Enzo Therapeutics, Inc. Compositions et procédés pour la formation et le remodelage osseux

Patent Citations (3)

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US6670387B1 (en) * 1998-12-17 2003-12-30 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2004076640A2 (fr) * 2003-02-25 2004-09-10 Ambion, Inc. Inhibiteurs d'angiogenine et de rnases a petites molecules et leurs procedes d'utilisation in vivo et in vitro
WO2009035430A2 (fr) * 2006-11-14 2009-03-19 Enzo Therapeutics, Inc. Compositions et procédés pour la formation et le remodelage osseux

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018094173A1 (fr) * 2016-11-18 2018-05-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Monomères de tgf-bêta modifiés et leur utilisation pour inhiber la signalisation de tgf-bêta
US11091523B2 (en) 2016-11-18 2021-08-17 University of Pittsburgh—of the Commonwealth System of Higher Education Engineered TGF-β monomers and their use for inhibiting TGF-β signaling

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