WO2022201063A1 - Composition de nanoparticules pour la dégradation ciblée de protéines - Google Patents

Composition de nanoparticules pour la dégradation ciblée de protéines Download PDF

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WO2022201063A1
WO2022201063A1 PCT/IB2022/052660 IB2022052660W WO2022201063A1 WO 2022201063 A1 WO2022201063 A1 WO 2022201063A1 IB 2022052660 W IB2022052660 W IB 2022052660W WO 2022201063 A1 WO2022201063 A1 WO 2022201063A1
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nanoparticle
disease
protein
pbm
pharmaceutically acceptable
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PCT/IB2022/052660
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English (en)
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Kalaipriya MADHAIYAN
Harini SRIRAM
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Covabind Joint Research Private Limited
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Publication of WO2022201063A1 publication Critical patent/WO2022201063A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle

Definitions

  • the present invention relates to nanoparticle composition comprising nanoparticle proteolysis targeting chimeras used for selectively inducing degradation of a targeted protein.
  • the present invention further relates to nanoparticle proteolysis targeting chimera comprising nanoparticle conjugated with ligand binding moiety that binds to target protein and E3 ligase binding moiety that binds to E3 ligase.
  • Targeted drug delivery ensures delivering increased concentration of the medication in some parts of the body relative to others.
  • the method reduces side effects and improves efficacy of the drug.
  • Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues.
  • Drug targeting implies delivery of drugs to receptors or organs to deliver the drugs exclusively.
  • the drug s therapeutic index, as measured by its pharmacological response and safety, relies in the access and specific introduction of the drug with its candidate receptor, whilst minimizing its introduction with non-target tissue.
  • the desired differential distribution of drug its targeted delivery would spare the rest of the body and thus significantly reduce the overall toxicity while maintaining its therapeutic benefits.
  • the targeted or site-specific delivery of drugs provides one of the most potential ways to improve the therapeutic index of the drugs.
  • PROTACs proteolysis targeting chimeras
  • Zou et al (The PROTAC technology in drug development, Cell BiochemFunct. 2019 Jan; 37(1): 21-30) reports a review summarizing the development of the PROTAC technology including peptide based PROTAC technology, small molecules based PROTACs, targeting different proteins and nuclear receptors for anti-cancer drug development.
  • PROTAC Proteolysis-targeting chimera
  • BRIM Bromodomain-containing protein 4
  • BTK Bruton’s tyrosine kinase
  • BCR- ABL BCR- ABL
  • MCL1 FMS-like tyrosine kinase 3
  • STAT3 Brg/Brahma-associated factors
  • WO2017201449 discloses antibody-(proteolysis-targeting chimera) (PROTAC) conjugate molecules their preparation a method and formulation thereof useful for facilitating intracellular degradation of target proteins.
  • WO2019199816 relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds.
  • WO2017044849 discloses compounds and compositions are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain- containing proteins and for treating and/or preventing certain diseases.
  • BET extra terminal
  • W02020038415 relates to bivalent compounds (e.g., bi-functional small molecule compounds) , compositions comprising one or more of the bivalent compounds, and to methods of use of the bivalent compounds for the treatment of certain diseases in a subject in need thereof.
  • the disclosure also relates to methods for identifying such bivalent compounds.
  • US225109362 provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and associated methods of use.
  • the bifunctional compounds are useful as modulators of targeted ubiquitination, especially with respect to estrogen receptor (ER), which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure, and the treatment of disease and conditions mediated by the ER, e.g. the treatment of breast cancer.
  • ER estrogen receptor
  • the PROTAC technology has a potential for development of drugs on the undruggable proteins.
  • the current successful PROTACs still largely used small molecules to target the druggable proteins with their inhibitors or ligands. This is mainly because the small molecules have good features of binding the targeted proteins.
  • it remains of an obstacle for the discovery of small molecule moiety to different targets.
  • One direction is to find a peptide epitope based on protein-protein interaction. This will open a broad way for the discovery of new drugs.
  • PROTACs are rendered as not ideal because of their poor physical properties as compared to traditional small molecule drugs.
  • Using PROTAC for drug development is promising but, its clinical application is a major concern. These concerns include the greater lipophilicity and poor aqueous solubility, off-target, cellular permeability, stability, and large molecular weight. Poor oral bioavailability has become a major issue leading to problems in understanding pharmcokinetics/pharmacodynamics (PK/PD) and translating pharmacology to higher species. Difficulty of synthesis of the hybrid molecule, including optimizing the linker length and composition are the other problems.
  • the current drugs developed through PROTAC technology have dual target, one for the target protein and one for the E3 Ligase.
  • W02020023549 provides, nanoparticle proteolysis targeting chimera s comprising compounds used to selectively induce the degradation of a target protein, their use as medicinal agents, and processes for their preparation.
  • the disclosure also provides for the use of the nanoparticle proteolysis targeting chimera s described herein as medicaments and/or in the manufacture of medicaments for the treatment of disease.
  • NPPROTAC Nanoparticle PROTAC replaces the linker of the PROTAC with a nanoparticle which conjugates the harmful target protein binder on one side of the molecules andE3 ligase binders on the other side ( Figure l).
  • the NPPROTAC facilitates cell permeability and even multiple binding with more target/E3 ligase proteins thus implementing degradation to a greater extent and wide application than with PROTACs.
  • Other advantages include more specific drug targeting and delivery, reduction in toxicity while maintaining therapeutic effects, improving the delivery of the drug conjugates into the cell thereby improving the bioavailability, greater safety and biocompatibility, and faster development of new safe medicines.
  • the inventors of the present invention have successfully formulated NPPROTAC replacing the linker of the PROTAC with a nanoparticle which conjugates the harmful target protein binder on one side (or peptide or oligonucleotide or antibody) to the E3 ligase binder on the other side.
  • the present invention provides a NPPROTAC system with multiple conjugation option, wider applicability and also facilitated delivery.
  • nanoparticle proteolysis targeting chimera s further comprise pharmaceutically acceptable carriers that interact with the compounds described herein to provide compositions in a form that is suitable for administration to a subject in need thereof.
  • the present invention provides to Nano-particle Proteolysis Targeting Chimeras (NPPROTAC) useful for targeted protein degradation.
  • NPPROTAC Nano-particle Proteolysis Targeting Chimeras
  • the invention provides the nanoparticle proteolysis targeting chimera for selectively induce protein degradation having compound of Formula (I) PBM-NP-EBM
  • PBM is ligand binding moiety that binds to target protein
  • NP is Nanoparticle connecting to EBM and PBM
  • EBM is E3 ubiquitin ligase binding moiety that binds to E3 ubiquitin ligase; and EBM is linked to PBM through nanoparticle NP.
  • the invention provides nanoparticle proteolysis targeting chimera having compound of formula (I) used to selectively induce degradation of a target protein.
  • the invention provides nanoparticle proteolysis targeting chimera comprising conjugated nanoparticles of compound of formula (I) used to selectively induce degradation of a target protein.
  • the nanoparticle proteolysis targeting chimera for selectively induce protein degradation wherein PBM is selected from compounds targeting to Human protein, small molecule, peptide, oligonucleotide and antibodies.
  • the present invention provides the nanoparticle proteolysis targeting chimera having compound of Formula (I), wherein PBM is binding moiety selected from but not limited to Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, Bromodomain containing protein BRD4 binder, CDK inhibitors, HDAC inhibitors, human lysine methyl transferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, compounds targeting the aryl hydrocarbon receptor (AHR), compounds targeting Aspartate decarboxylase (PanD), compounds targeting Glutathione-S-transferase (GSTal) and compounds targeting pseudokinase ErbB3.
  • PBM is binding moiety selected from but not limited to Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, Bromodomain containing protein BRD4 binder, CDK inhibitors, HDAC inhibitors, human lysine
  • the present invention provides the nanoparticle proteolysis targeting chimera having compound of Formula (I), wherein EBM is selected from but not limited a cereblon binder, a Von Hippel-Lindau tumor suppressor protein (VHL) binder, an inhibitor of apoptosis protein (LAP) binder, a Kelch-like ECH-associated protein 1 (Keapl) binder, a mouse double minute 2 homolog (MDM2) binder, and beta-transducin repeat containing protein (b-TrCP) binder.
  • EBM is a cereblon binder.
  • EBM is a cereblon binder selected from lenalidomide, pomalidomide, thalidomide or analogue thereof.
  • the nanoparticle proteolysis targeting chimera for selectively induce protein degradation wherein NP is nanoparticle selected from but not limited to Nanodiamond, liposomes, dendrimer, polymeric nanoparticle, metal and metal oxide.
  • polymeric nanoparticle fabricated using polymer but not limited to PCL, PLGA, PLACL, PLLA.
  • metallic nanoparticle prepared using but not limited to metal such as Au, Ag and metal oxide such as FesCE, AI2O3.
  • NP is Nanodiamond particle; More particularly, Nanodiamond conjugated with EBM (E3 ubiquitin ligase binding moiety) and PBM (protein binding moiety).
  • NP is Nanodiamond.
  • size of nanoparticle is ranging from 100 to 500 nm, both inclusive.
  • the nanoparticle proteolysis targeting chimera for selectively induce protein degradation having compounds of Formula (I) and methods for their preparation.
  • the invention provides the nanoparticle proteolysis targeting chimera for selectively induce protein degradation having compound of formula (II)
  • PBM is Bromodomain containing protein BRD4 binder
  • ND is Nanodiamond
  • EBM is cereblon E3 ubiquitin ligase binding moiety capable of binding a cereblon E3 ubiquitin ligase in a cell, ortautomers or a stereoisomer or pharmaceutically acceptable salt thereof; wherein, ND conjugated with cereblon E3 ubiquitin ligase binding moiety and Bromodomain containing protein BRD4 binder.
  • the invention provides the nanoparticle proteolysis targeting chimera for selectively induce protein degradation having compound of formula (II) PBM-ND-EBM
  • PBM is JQ1 piperazinamide
  • ND is Nanodiamond conjugated with cereblon E3 ubiquitin ligase binding moiety and JQ1 piperazinamide
  • EBM is selected from thalidomide, pomalidomide, lenalidomide, or an analog thereof.
  • the invention provides the nanoparticle proteolysis targeting chimera for selectively induce protein degradation comprises compound 1 : or tautomers or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the invention provides the nanoparticle proteolysis targeting chimera for selectively induce protein degradation comprising compounds of Formula (II) and methods of their preparation.
  • the invention provides pharmaceutical composition comprises the nanoparticle proteolysis targeting chimera for selectively induce protein degradation.
  • the invention provides a pharmaceutical composition as described herein above, to be administered using pharmaceutically acceptable dosage form.
  • the invention provides a method of treating a disease in a subject in need thereof by administering the compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating a disease associated with a bromodomain or a bromodomain-containing protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof; wherein the disease is a proliferative disease, inflammatory disease, cardiovascular disease, autoimmune disease, viral infection, fibrotic disease, neurological disease, metabolic disease, or endocrine disease.
  • the present invention provides the use of the nanoparticle proteolysis targeting chimera having compound of formula (I) described hereinabove as medicaments and/or in the manufacture of medicaments for the treatment of a disease.
  • the present invention provides nanoparticle proteolysis targeting chimera of Compound 1 :
  • ligand binding moiety is but not limited to an amine functionalized JQ1 piperazinamide:
  • nanoparticle conjugated with cereblon E3 ubiquitin ligase binding moiety and JQ1 piperazinamide is Nanodiamond.
  • E3 ubiquitin ligase binding moiety is selected from but not limited to: or analogue thereof or tautomers or a stereoisomer or pharmaceutically acceptable salt thereof.
  • the invention provides process of preparing the Compound 1.
  • the nanoparticles are associated with (e.g., bound to or connected to) the PBM and/or EBM via functionalization of the nanoparticle.
  • a nanoparticle is connected to PBM and/or EBM via formation of a bond, such as an ionic bond, a covalent bond, a hydrogen bond, Van der Waals interactions, and the like.
  • the covalent bond may be, for example, a carbon-carbon, carbon-oxygen, oxygen-silicon, sulfur- sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, or other covalent bond.
  • the hydrogen bond may be, for example, between hydroxyl, amine, carboxyl, thiol, and/or similar functional groups.
  • the PBM and/or EBM may include a functional group, such as a thiol, aldehyde, ester, carboxylic acid, hydroxyl, and the like, wherein the functional group forms a bond with the nanoparticle.
  • the PBM and/or EBM may be an electron-rich or electron-poor moiety wherein interaction between the nanoparticle and the PBM and/or EBM comprises an electrostatic interaction.
  • the description provides therapeutic compositions comprising an effective amount of a compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier.
  • the therapeutic compositions modulate protein degradation in a patient or subject, for example, an animal such as a human, and can be used for treating or ameliorating disease states or conditions which are modulated through the degraded protein.
  • the therapeutic compositions as described herein may be used to effectuate the degradation of proteins of interest for the treatment or amelioration of a disease, e.g. cancer.
  • the present disclosure provides a method of ubiquitinating / degrading a target protein in a cell.
  • A denotes small molecule Target protein degradation principle
  • C denotes nanoparticle mediated target protein degradation principle.
  • Figure 2. Illustration of FTIR spectra of NPPROTAC and control.
  • Figure 3. Illustration of FTIR spectra comparison of NPPROTACs.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the a disease disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist.
  • target protein refers to a protein or polypeptide, which is a target for binding to a compound according to the present invention and degradation by ubiquitin ligase hereunder.
  • target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest.
  • binding moieties are linked to a compound that binds to an E3 ubiquitin ligase through a linker (ND as nanoparticle described in Formula (I) herein).
  • Ubiquitin Ligase or “E3 ubiquitin ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation.
  • cereblon is an E3 Ubiquitin Ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysine on ubiquitin can be targeted by an E3 to make chains.
  • lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
  • References herein to a “Nanodiamond” should be understood as a reference to a nanoparticle. Nanodiamond is functionalized to obtain the “Nanodiamond acid. References herein in the singular tense to a particular particle type, such as a Nanodiamond including nanoparticle, may also be extended to a plurality of particle, unless the context requires otherwise.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives, including prodrug and/or deuterated forms thereof where applicable, in context.
  • Deuterated small molecules contemplated are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium.
  • the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. When the bond is shown, both a double bond and single bond are represented or understood within the context of the compound shown and well-known rules for valence interactions.
  • the compounds of the invention may form salts with acid or base.
  • the compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts.
  • Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases.
  • the compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of PBM and EBM” can refer, in one embodiment, to at least one, optionally including more than one, PBM, with no EBM present (and optionally including elements other than EBM); in another embodiment, to at least one, optionally including more than one, EBM, with no PBM present (and optionally including elements other than PBM); in yet another embodiment, to at least one, optionally including more than one, PBM, and at least one, optionally including more than one, EBM (and optionally including other elements); etc.
  • bioactive agent is used to describe an agent, other than a compound according to the present disclosure, which is used in combination with the present compounds as an agent with biological activity to assist in effecting an intended therapy, inhibition and/or prevention/prophylaxis for which the present compounds are used.
  • Preferred bioactive agents for use herein include those agents which have pharmacological activity similar to that for which the present compounds are used or administered and include for example, anti-cancer agents, antiviral agents, especially including anti-HIV agents and anti-HCV agents, antimicrobial agents, antifungal agents, etc.
  • diseased state or condition is used to describe any diseased state or condition wherein protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and where degradation of one or more proteins in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof. In certain instances, the diseased state or condition may be cured.
  • co-administration and “co-administering” or “combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
  • one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, especially including an anticancer agent.
  • the co- administration of compounds results in synergistic activity and/or therapy, including anticancer activity. It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method are not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.
  • compositions comprising combinations of an effective amount of at least one bifunctional compound as described herein, and one or more of the compounds otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present disclosure.
  • the present disclosure includes, where applicable, the compositions comprising the pharmaceutically acceptable salts, in particular, acid or base addition salts of compounds as described herein.
  • the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful according to this aspect are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1 '-methyl ene-bis-(2 -hydroxy-3 naphthoate)] salts, among numerous others.
  • non-toxic acid addition salts i.e., salts containing pharmacological
  • Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eg., potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.
  • the compounds as described herein may, in accordance with the disclosure, be administered in single or divided doses by the oral, parenteral or topical routes.
  • Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, among other routes of administration.
  • Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration.
  • Themost effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient.
  • compositions comprising an effective amount of compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
  • Compounds according to the present disclosure ion may be administered in immediate release, intermediate release or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of compound at an injection site.
  • compositions as described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled- release formulations.
  • Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions as described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions as described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
  • compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions as described herein may be administered in the form of suppositories for rectal administration.
  • compositions as described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-acceptable transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the compounds may be coated onto a stent which is to be surgically implanted into a patient in order to inhibit or reduce the likelihood of occlusion occurring in the stent in the patient.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions as described herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions should be formulated to contain between about 0.05 milligram to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one other compound according to the present disclosure.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.
  • a patient or subject in need of therapy using compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of the compound according to the present disclosure including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known erythropoiesis stimulating agents as otherwise identified herein.
  • These compounds can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or by aerosol form.
  • the description provides therapeutic compositions comprising an effective amount of a compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier.
  • the therapeutic compositions modulate protein degradation in a patient or subject, for example, an animal such as a human, and can be used for treating or ameliorating disease states or conditions which are modulated through the degraded protein.
  • the description provides therapeutic compositions as described herein for effectuating the degradation of proteins of interest for the treatment or amelioration of a disease, e.g., cancer.
  • a disease e.g., cancer.
  • the disease is multiple myeloma.
  • the description provides a method of ubiquitinating/degrading a target protein in a cell.
  • the method comprises administering a bifunctional compound as described herein comprising, e.g., a EBM and a PBM, preferably linked through nanoparticle, as otherwise described herein, wherein the EBM is coupled to the PBM and wherein the EBM recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase such as, e.g., cereblon) and the PBM recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation/inhibition of the effects of the target protein and the control of protein levels.
  • a ubiquitin pathway protein e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase such as, e.g., cereblon
  • the PBM recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity
  • control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cell, e.g., cell of a patient.
  • the method comprises administering an effective amount of a compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or combination thereof.
  • the description provides methods for treating or emeliorating a disease, disorder or symptom thereof in a subject or a patient, e.g., an animal such as a human, comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein or salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or combination thereof, wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.
  • the description provides methods for identifying the effects of the degradation of proteins of interest in a biological system using compounds according to the present disclosure.
  • the present disclosure is directed to a method of treating a human patient in need for a disease state or condition modulated through a protein where the degradation of that protein will produce a therapeutic effect in that patient, the method comprising administering to a patient in need an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.
  • the disease state or condition may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacteria, fungus, protozoa or other microbe or may be a disease state, which is caused by overexpression of a protein, which leads to a disease state and/or condition
  • ND-COOH powder was suspended in DMF and sonicated well before conjugated with peptide.
  • HATU and DIEA were added to ND-COOH suspensions to activate the carboxyl groups in ND-COOH.
  • PBM e.g JQ1- Piperazine
  • LBM e.g. Pomalidomide/Lenalidomide/Thalidomide
  • ND-COOH powder was suspended in DMF (2.5 mg/mL) and sonicated well before conjugated with peptide.
  • 10 mg of HATU and 15 uL of DIEA were added to 2.5 mL ND- COOH suspensions to activate the carboxyl groups in ND-COOH.
  • JQ1 -Piperazine was added into the reaction suspension at a weight ratio of 1:1 (2.5mg of JQ1 -Piperazine to ND-COOH).
  • the reaction mixture was centrifuged at 15,000 rpm for 10 15 min.
  • the precipitates (ND-CONH-JQ1) were re-suspended in deionized water. Unreacted amines, together with HATU and DIEA, remained in the supernatant and were collected for quantifying conjugation efficiency.
  • ND-COOH powder was suspended in DMF (2.5 mg/mL) and sonicated well before conjugated with peptide. 10 mg of HATU and 15 uL of DIEA were added to 2.5 mL ND-COOH suspensions to activate the carboxyl groups in ND-COOH. After 10 min of activation at room temperature, Lenalidomide was added into the reaction suspension at a weight ratio of 1:1 (2.5mg of Lenalidomide to ND-COOH for synthesis of NDCONH-Len). Following reaction at room temperature overnight, the reaction mixture was centrifuged at 15,000 rpm for 15 min. Subsequently, the precipitates (ND-CONHLen) were re-suspended in deionized water.
  • JQ1 -Piperazine and Lenalidomide were added into the reaction suspension at a weight ratio of 1:1 (2.5 mg of JQ1 -Piperazine + 2.5 mg of Lenalidomide to ND-COOH).
  • the reaction mixture was centrifuged at 15,000 rpm for 15 min. Subsequently, the precipitates (ND-CONH-JQl/Len) were re suspended in deionized water. Unreacted amines, together with HATU and DIEA, remained in the supernatant and were collected for quantifying conjugation efficiency.
  • ND-PG protecting group
  • ND-PG-N3 was reacted with E3 ligase binding peptide bearing an alkynyl terminal through cooper-catalyzed click reaction to yield ND-PG-E3 ligase binding peptide.
  • E3 ligase binding peptide bearing an alkynyl terminal through cooper-catalyzed click reaction to yield ND-PG-E3 ligase binding peptide.
  • partial hydroxyl groups on mitsunobu reaction chemistry was used.
  • E3 ligase binding peptides were used for binding with VHL, IAP or similar E3 ligases.
  • Cell penetrating peptide is used to facilitate cell permeability and Fluorescent Tags were used to study internalisation of the nanoparticle.
  • the zeta potential shows level of repulsion between adjacent; likewise charged particles in scattering and its value can be identified to determine the stability of the nanoparticles (Figure
  • the degradation of the target protein was analyzed using SDS-PAGE and/or western blot performed using the cell lysate obtained from cultured cells post treatment using NPPROTAC.
  • the degradation of the target protein can be determined by the smearing of the band and migration into several lower molecular weight bands rather than a single band at a molecular weight corresponding to the target protein.
  • Alpha CETSA® Alpha Cellular Thermal Shift assays

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Abstract

L'invention concerne des chimères ciblant la protéolyse de nanoparticules utilisées pour induire sélectivement la dégradation d'une protéine ciblée. Plus particulièrement, l'invention concerne une composition de nanoparticules comprenant un composé de formule (I), leur utilisation en tant qu'agent médicinal et leur procédé de préparation.
PCT/IB2022/052660 2021-03-23 2022-03-23 Composition de nanoparticules pour la dégradation ciblée de protéines WO2022201063A1 (fr)

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WO2019014429A1 (fr) * 2017-07-12 2019-01-17 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation de la protéine tau

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019014429A1 (fr) * 2017-07-12 2019-01-17 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation de la protéine tau

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHAN KWOK-HO, ZENGERLE MICHAEL, TESTA ANDREA, CIULLI ALESSIO: "Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 2, 25 January 2018 (2018-01-25), US , pages 504 - 513, XP055930443, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01912 *
LIU ZHIQING, WANG PINGYUAN, CHEN HAIYING, WOLD ERIC A., TIAN BING, BRASIER ALLAN R., ZHOU JIA: "Drug Discovery Targeting Bromodomain-Containing Protein 4", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 60, no. 11, 8 June 2017 (2017-06-08), US , pages 4533 - 4558, XP055933167, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01761 *

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