WO2022255779A1 - Molécule chimère protac de jak et composition pharmaceutique la contenant pour le traitement ou la prévention d'une maladie liée à jak - Google Patents

Molécule chimère protac de jak et composition pharmaceutique la contenant pour le traitement ou la prévention d'une maladie liée à jak Download PDF

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WO2022255779A1
WO2022255779A1 PCT/KR2022/007750 KR2022007750W WO2022255779A1 WO 2022255779 A1 WO2022255779 A1 WO 2022255779A1 KR 2022007750 W KR2022007750 W KR 2022007750W WO 2022255779 A1 WO2022255779 A1 WO 2022255779A1
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protein
jakpp
jak
binding domain
chimeric molecule
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PCT/KR2022/007750
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English (en)
Korean (ko)
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전영호
변영주
김은지
손상현
김호순
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주식회사 에즈큐리스
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to a novel JAK protac derivative, a method for preparing the same, and a pharmacological composition for treating or preventing JAK-related diseases including the same. Since it binds to the degradation system regulator E3 ligase and exhibits excellent effects on intracellular JAK protein degradation, it can be usefully used as a pharmaceutical composition for preventing/treating allergic diseases such as asthma or atopy and cancer.
  • PROTAC is an abbreviation of proteolysis targeting chimera, which induces intracellular proteolysis to selectively remove unwanted proteins.
  • Protac is a heterodimeric molecule in which a ligand of a target protein and a ligand binding to E3 ligase are connected through a linker. Protac binds to both proteins simultaneously, bringing the target protein into close proximity to the E3 ligase, which recognizes the target protein as a substrate and triggers polyubiquitination and subsequent proteasomal degradation.
  • the N-degron pathway is a system that degrades proteins by recognizing N-terminal amino acids of substrate proteins.
  • the N-terminal amino acids of substrate proteins are recognized by the UBR E3 ubiquitin ligase family to ubiquitinate and protease substrate proteins. It goes through the process of decomposition by moths. Protac uses this principle to bring proteins that were physically different from each other closer together and can effectively remove specific proteins from cells. Whereas existing drugs must bind to a specific active site or binding site that can inhibit the function of a target protein, Protac can only bind to a target protein close to a position where it can be degraded, regardless of the binding site. If present, it has the advantage of inhibiting the function by degrading the target protein. In this respect, Protac has high potential as a therapeutic agent for diseases.
  • Janus kinase (hereinafter referred to as 'JAK') is a cytoplasmic protein tyrosine kinase that plays a central role in regulating cell functions in the lympho-hematopoietic system.
  • JAK activates STAT (Signal Transducer and Activators of Transcription) protein through tyrosine phosphorylation, and provides a rapid signal transduction pathway to cytokines.
  • JAK/STAT signaling has been implicated in allergy, asthma, autoimmune diseases (e.g. transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis), solid tumors, and hematological cancers (e.g. leukemia, lymphoma, etc.). It is known.
  • the JAK protein family is divided into four types: JAK1, JAK2, JAK3, and Tyk2. Currently, several pharmaceutical companies are trying to develop new drugs with excellent JAK protein inhibitory activity.
  • the present inventors confirmed that the novel JAK protac derivative exhibits excellent effects on the degradation of intracellular JAK protein and completed the present invention, which can be usefully used for the treatment and prevention of JAK-related diseases.
  • An object of the present invention is to provide a chimeric molecule comprising a JAK protein binding domain, a ubiquitin ligase binding domain, and a linker domain linked to the ubiquitin ligase binding domain and the protein binding domain.
  • an object of the present invention is to provide a pharmaceutical composition for treating or preventing JAK protein-related diseases, including the chimeric molecule.
  • an object of the present invention is to provide a method for preventing or treating a JAK protein-related disease, comprising administering the chimeric molecule to a subject in need thereof.
  • an object to be solved by the present invention is to provide a use of the chimeric molecule for preparing a medicament for use in preventing or treating a JAK protein-related disease.
  • an object of the present invention is to provide a pharmaceutical composition comprising the chimeric molecule and a pharmaceutically acceptable additive.
  • the present invention provides a chimeric molecule comprising a JAK protein binding domain, a ubiquitin ligase binding domain, and a linker domain linked to the ubiquitin ligase binding domain and the protein binding domain.
  • the protein binding domain may bind to any one JAK protein selected from the group consisting of JAK1 protein, JAK2 protein and JAK3 protein.
  • the protein binding domain may be characterized in that it is a peptide comprising any one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 18.
  • the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 1, and the JAK protein may be a JAK2 protein.
  • the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 8, and the JAK protein may be a JAK3 protein.
  • the protein binding domain may be a peptide including the amino acid sequence of SEQ ID NO: 14, and the JAK protein may be a JAK1 protein.
  • the ubiquitin ligase binding domain may be characterized by binding to E3 ubiquitin ligase, UBR1 (ubiquitin-protein ligase E3 component n-recognin 1) or UBR2 (ubiquitin-protein ligase E3 component n- recognized 2).
  • another embodiment of the present invention provides a pharmaceutical composition for treating or preventing JAK protein-related diseases including the chimeric molecule.
  • the pharmaceutical composition may be a pharmaceutical composition for treatment or prevention of a disease selected from the group consisting of asthma, allergic dermatitis, atopic dermatitis, psoriasis and cancer.
  • Another embodiment of the present invention provides a pharmaceutical composition comprising the chimeric molecule and a pharmaceutically acceptable additive.
  • novel JAK protac derivative according to the present invention binds to the ubiquitin proteosome proteolysis system regulator E3 ligase, exhibits excellent effects in degrading JAK protein in cells, and prevents/treats allergic diseases such as asthma and atopy and cancer. effective for
  • peptide may refer to a linear molecule formed by binding amino acid residues to each other through a peptide bond.
  • the term “Protak” is a proteolysis targeting chimera, which is a heterodimeric molecule in which a ligand of a target protein and a ligand binding to ubiquitin ligase are connected through a linker.
  • the JAK protak chimera molecule in which the JAK protein binding domain and the ubiquitin ligase binding domain are linked by a linker domain is a fusion protein in which the two protein domains are linked through a linker while maintaining their respective functions.
  • chimeric molecule generally refers to a molecule made up of two or more different domains or structures that are not found together as a single molecule in nature.
  • derivative in the present invention may mean a peptide modified by chemically modifying the N-terminus or C-terminus of the peptide of the present invention or by adding amino acids, but is not limited thereto. It may mean a peptide that performs the same or similar function as the peptide.
  • the peptide may be prepared by direct chemical synthesis using solid phase peptide synthesis, synthesis using an automatic synthesizer, or by inserting a base sequence encoding the peptide into a vector and expressing it. It is not limited to this.
  • the ubiquitin ligase binding domain binds to E3 ubiquitin ligase
  • the E3 ubiquitin ligase is Cereblon E3 ligase, ubiquitin-protein ligase E3 component n-recognin 1 (UBR1) ), ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) or ubiquitin-protein ligase E3 component n-recognin 4 (UBR4).
  • the JAK protein binding domain and the ubiquitin ligase binding domain are bonded to each other through a linker, and the linker connects the protein binding domain and the ubiquitin ligase binding domain directly/indirectly, covalently/non-covalently, It can be connected in a flexible / inflexible manner, and the linker domain can be of a length sufficient to effectively position the ubiquitin ligase and the target protein in close proximity.
  • linkers commonly known in the art can be used in the chimeric molecules according to the present invention.
  • a JAK protak chimeric molecule was prepared by combining -(Arg) 10 - with the linker -Ahx-Ahx- with the ubiquitin ligase binding domain, but it is not limited thereto, and those skilled in the art A variety of known ubiquitin ligase binding domains and linkers that can be readily selected can be used.
  • JAK peptide protac derivatives and physicochemical properties prepared in the present invention are shown in Table 1 below.
  • JAKPP 4 JAKPP 14 and JAKPP 15 were prepared for use in a pull-down assay for confirming binding ability to URB.
  • JAKPP 5 and JAKPP 6 were designed to include a C-C covalent bond at the N-terminus to increase the half-life of the peptide.
  • JAKPP 1 to 6 are protac sequences targeting JAK2, and among them, JAKPP 5 was most effective in degrading the JAK2 protein.
  • JAKPP 7 and JAKPP 8 were prepared using JAK1 as a target protein, JAKPP 9 using JAK3 as a target protein, and JAKPP 10 to JAKPP 13 were prepared by modifying Protak JAKPP 7.
  • Protak JAKPP 9 was effective in degrading JAK3 protein
  • JAKPP 12 was effective in degrading JAK1 protein because the sequence was prepared with the JAK3 target protein.
  • the target protein is recognized by the ubiquitin ligase and the protein is It undergoes ubiquitination and degradation by the proteasome.
  • the composition of the present invention may include pharmaceutically acceptable salts, carriers, excipients, diluents, solubilizers, and the like.
  • the pharmaceutically acceptable salt refers to a salt commonly used in the pharmaceutical industry, and includes, for example, sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, iron and salts of inorganic ions and hydrochloric acid,
  • inorganic acids such as phosphoric acid and sulfuric acid
  • organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotate acid, and acetylsalicylic acid.
  • amino acid salts such as lysine, arginine, and guanidine.
  • organic ion salts such as tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, benzyl trimethyl ammonium, and benzethonium that can be used in pharmaceutical reactions, purification and separation processes.
  • the types of salts meant in the present invention are not limited by these listed salts.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline quality cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, and solubilizing agents include poloxamer and labrasol; Not limited to this.
  • the pharmaceutical composition of the present invention can be prepared into a pharmaceutical formulation using methods well known in the art.
  • the active ingredient may be mixed or diluted with a carrier, or encapsulated in a carrier in the form of a container.
  • the pharmaceutical composition of the present invention can be formulated into tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • the pharmaceutical composition may be administered orally, rectally, transdermally, intravenously, intramuscularly, intraperitoneally, intramedullarily, intrathecally or subcutaneously.
  • Formulations for oral administration may be tablets, pills, soft or hard capsules, granules, powders, solutions or emulsions, but are not limited thereto.
  • Formulations for parenteral administration may be injections, drops, lotions, ointments, gels, creams, suspensions, emulsions, suppositories, patches or sprays, but are not limited thereto.
  • the pharmaceutical composition may include additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, flavors, or sweeteners, if necessary.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • HMC 1.1 cells were treated with 10% antibiotics.
  • FBS and 1% antibiotics were added using Iscove's Modified Dulbecco's Medium (IMDM, HyClone) and cultured in an incubator maintained at 5% CO 2 and 37 °C.
  • UBR1 pcDNA3.1-hUBR1-his6
  • UBR2 pcDNA3.1-hUBR2-his6
  • JAKPP 4 JAKPP 14 and JAKPP 15 were each bound to bulk streptavidin agarose resin (Thermo). 300 ⁇ g of the HEK293T cell extract transfected with UBR1 and UBR2 was added to a JAKPP 4-conjugated streptavidin agarose gel, JAKPP 14-conjugated streptavidin agarose gel, and JAKPP 15-conjugated streptavidin agarose gel, followed by 4 It was reacted for 3 hours at °C. After the reaction, samples were prepared for one-dimensional electrophoresis.
  • Cycloheximide (CHX (Calbiochem) was diluted to 200 ⁇ g/mL in the culture medium.
  • HMC 1.1 cells which are non-adherent cells, were centrifuged from cells in a culture flask filled to about 80%, and then 2.5 x 10 5 were placed in IMDM medium containing 200 ⁇ g/mL of CHX (10% FBS, 1% antibiotics). Incubated for more than 1 hour in 3 mL.
  • JAK-protak peptide was prepared at a concentration of 10 mM in tertiary distilled water. Each 10 mM JAK-Protak peptide stock solution was treated with CHX-pretreated HMC 1.1 cells at concentrations of 10 ⁇ M, 25 ⁇ M, 30 ⁇ M, 50 ⁇ M or 90 ⁇ M and incubated for 6 hours, depending on the JAK-Protak peptide used. Incubated for 12 or 24 hours.
  • the JAK-Protak peptide sequence used is as described in Tables 1 and 2 above.
  • RIPA buffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1% NP-40, 1% NP-40, 1% sodium deoxycholate) was added, the cells were uniformly released by vortex, and then the cells were pulverized with a sonicator while maintaining the condition of 4 °C. After grinding, centrifugation was performed at 14,000 xg for 30 minutes, the supernatant was taken, and protein was quantified by a BCA (Thermo Fisher scientific) method so that the protein concentration of the cell extract was 1-2 mg/ml.
  • BCA Thermo Fisher scientific
  • 5X one-dimensional SDS-PAGE buffer 0.5M Tris-HCl, pH 6.8, 10% SDS, 10% ⁇ -mercaptoethanol, 30% glycerol, 0.2% bromophenol blue
  • a 1.0 mm or 1.5 mm thick 8% or 12% acrylamide separation gel (pH 8.8) was prepared using an acryl-bis acrylamide solution (40%, 29:1, v/v), on which 5% was stacked.
  • a gel (pH 6.8) was made and used. 25 ⁇ g of protein sample was added using 15 wells of the stacking gel. After stacking at 70-80 V/hr, separation was performed at 150-180 V/hr until the JAK2 protein location could be distinguished.
  • the separated proteins were electrophoresed through a polyvinylidene fluoride (PVDF) membrane at 60 V/hr for 100 minutes.
  • PVDF membrane on which the protein was electrophoresed was blocked in 1X TBS-T buffer solution (25 mM Tris, 150 mM NaCl, 0.1% tween-20, pH 7.4) containing 5% bovine serum albumin (BSA) for 1 hour, and then the same
  • BSA bovine serum albumin
  • Each antibody was diluted in a buffer solution and reacted at 4° C. for 12 hours.
  • the UBR1 antibody (abCam, ab138267) was diluted 1000:1, and the UBR2 antibody (Bioworld, BS60150) was diluted 1000:1.
  • JAK2 antibody (Cell signaling, 3230S) was diluted 500:1, and ⁇ -Actin antibody (Cell signaling, 3700S) was diluted 1000:1.
  • the cells were washed 5 times for 5 minutes each with 1X TBS-T.
  • HRP horseradish peroxidase
  • HRP horseradish peroxidase
  • JAKPP 4, JAKPP 14, JAKPP 15, UBR1, and UBR2 in HEK293T cells were confirmed.
  • 300 ⁇ g of HEK293T cell extract was incubated on a streptavidin agarose gel to which JAK2-Protac (JAKPP 4, JAKPP 14, and JAKPP 15) were conjugated at 4° C. for 3 hours.
  • JAK2-Protac JAK2-Protac
  • JAKPP 4 binds to UBR1 more than twice as strongly as JAKPP 14 and JAKPP 15.
  • JAKPP 14 and JAKPP 15 there was no difference in the degree of binding of JAKPP 4, JAKPP 14 and JAKPP 15 to UBR2 (FIG. 1).
  • Arrows in FIG. 1 indicate UBR 1 and UBR2, respectively, and Input 2% indicates HEK293T cell crude extract 60 ⁇ g, and Input 1% indicates HEK293T cell crude extract 30 ⁇ g.
  • HMC1.1 cells were treated with cyclohexamid 200 ⁇ g/mL for 6 hours in the presence and absence of JAK2-Protac (JAKPP 4, JAKPP 14, and JAKPP 15) at 10 ⁇ M or 30 ⁇ M, respectively.
  • Cell extracts 25 ⁇ g were subjected to immunoblot with JAK2 or ⁇ -Actin specific antibodies after SDS-PAGE gel.
  • FIG. 2 arrows indicate JAK2 and ⁇ -Actin, and Veh indicates a vehicle.
  • HMC1.1 cells were treated with 200 ⁇ g/mL of cyclohexamide for 12 hours in the presence and absence of JAK2-Protac (JAKPP 1, JAKPP 2, and JAKPP 3) at 10 ⁇ M or 90 ⁇ M, respectively.
  • JAK2-Protac JAK2-Protac
  • Cell extracts 50 ⁇ g were subjected to immunoblot with JAK2 or ⁇ -Actin specific antibodies after SDS-PAGE gel.
  • JAK2 protein present in the human mast cell line HMC1.1 was reduced by about 10% when 90 ⁇ M of JAKPP 1 was treated.
  • JAK2 protein present in the human mast cell line HMC1.1 was reduced by about 30% when JAKPP 2 was treated with 90 ⁇ M (FIG. 3).
  • arrows indicate JAK2 and ⁇ -Actin
  • Veh indicates a vehicle.
  • JAK2-Protac (JAKPP 1 , JAKPP 4 , JAKPP 5 and HMC1.1 cells were treated with cyclohexamid 200 ⁇ g/mL for 24 hours in the presence and absence of JAKPP 6) at 10 ⁇ M or 30 ⁇ M, respectively.
  • Cell extracts (25 ⁇ g) were subjected to immunoblot with JAK2 or ⁇ -Actin specific antibodies after SDS-PAGE gel.
  • JAK2 protein present in the human mast cell line HMC1.1 was reduced by more than 30% when treated with 30 ⁇ M of JAKPP 1 or 30 ⁇ M of JAKPP 4, respectively.
  • the JAK2 protein present in the human mast cell line HMC1.1 was reduced by more than 50% when treated with 30 ⁇ M of JAKPP 5 (FIG. 4).
  • arrows indicate JAK2 and ⁇ -Actin
  • Veh indicates a vehicle.
  • HMC1.1 cells were treated with cyclohexamid 200 ⁇ g/mL for 24 hours in the presence and absence of JAK-Protac (JAKPP 7, JAKPP 8, and JAKPP 9) at 25 ⁇ M, respectively.
  • Cell extracts (20 ⁇ g) were subjected to SDS-PAGE gel followed by immunoblot with JAK1, JAK3 or ⁇ -Actin specific antibodies.
  • HMC1.1 cells were cultured in the presence and absence of JAK-Protac (JAKPP 10, JAKPP 11, JAKPP 12, and JAKPP 13) at 25 ⁇ M or 50 ⁇ M, respectively, with cyclohexamid 200 ⁇ g/mL for 24 hours. processed. Cell extracts (20 ⁇ g) were subjected to SDS-PAGE gel followed by immunoblot with antibodies specific for JAK1, JAK2 or ⁇ -Actin.
  • JAK1 protein present in the human mast cell line HMC1.1 was reduced by 70% when treated with 50 ⁇ M JAKPP 12, or by 40% when treated with 50 ⁇ M JAKPP 13. Meanwhile, JAK2 protein was not reduced under the same conditions (FIG. 6).
  • arrows indicate JAK1 or JAK2 or ⁇ -Actin and Veh indicates vehicle.
  • the present invention relates to a novel JAK protac derivative, a method for preparing the same, and a pharmacological composition for treating or preventing JAK-related diseases including the same. Since it binds to the degradation system regulator E3 ligase and exhibits excellent effects on intracellular JAK protein degradation, it can be usefully used as a pharmaceutical composition for preventing/treating allergic diseases such as asthma or atopy and cancer.

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Abstract

La présente invention concerne un nouveau dérivé PROTAC de peptide JAK, son procédé de préparation, et une composition pharmaceutique le contenant pour le traitement ou la prévention d'une maladie liée à JAK. Le nouveau dérivé PROTAC de peptide JAK selon la présente invention est associé à la ligase E3 du régulateur du système de protéolyse de l'ubiquitine ligase pour présenter un excellent effet sur la dégradation du peptide JAK dans les cellules et est efficace pour le traitement ou la prévention d'une maladie liée au peptide JAK.
PCT/KR2022/007750 2021-06-01 2022-05-31 Molécule chimère protac de jak et composition pharmaceutique la contenant pour le traitement ou la prévention d'une maladie liée à jak WO2022255779A1 (fr)

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Citations (2)

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WO2020200291A1 (fr) * 2019-04-02 2020-10-08 Cullgen (Shanghai) , Inc. Composés et méthodes de traitement de cancers
US20210107949A1 (en) * 2016-03-19 2021-04-15 Exuma Biotech Corp. Methods and compositions for genetically modifying lymphocytes to express polypeptides comprising the intracellular domain of mpl

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Publication number Priority date Publication date Assignee Title
EP2077279B1 (fr) 2000-06-28 2012-09-05 Amgen Inc. Molécules de récepteur de lymphopoiétine stromale thymiques et utilisations associées

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Publication number Priority date Publication date Assignee Title
US20210107949A1 (en) * 2016-03-19 2021-04-15 Exuma Biotech Corp. Methods and compositions for genetically modifying lymphocytes to express polypeptides comprising the intracellular domain of mpl
WO2020200291A1 (fr) * 2019-04-02 2020-10-08 Cullgen (Shanghai) , Inc. Composés et méthodes de traitement de cancers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KARGBO ROBERT B.: "Degradation of Janus Kinase for Potential Application in Immune Response Therapeutics", ACS MEDICINAL CHEMISTRY LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 12, no. 3, 11 March 2021 (2021-03-11), US , pages 316 - 317, XP093010376, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.1c00058 *
SHAH RISHI R.; REDMOND JOANNA M.; MIHUT ANDREI; MENON MALINI; EVANS JOHN P.; MURPHY JOHN A.; BARTHOLOMEW MICHELLE A.; COE DIANE M.: "Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 5, 23 January 2020 (2020-01-23), AMSTERDAM, NL, XP086045160, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2020.115326 *
YONGHAN HE, KHAN SAJID, HUO ZHIGUANG, LV DONGWEN, ZHANG XUAN, LIU XINGUI, YUAN YAXIA, HROMAS ROBERT, XU MINGJIANG, ZHENG GUANGRONG: "Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies", JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 13, no. 1, XP055751965, DOI: 10.1186/s13045-020-00924-z *

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