WO2021223026A1 - Peptides à inactivation ezh1/2, procédés et utilisations de ceux-ci - Google Patents

Peptides à inactivation ezh1/2, procédés et utilisations de ceux-ci Download PDF

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Publication number
WO2021223026A1
WO2021223026A1 PCT/CA2021/050628 CA2021050628W WO2021223026A1 WO 2021223026 A1 WO2021223026 A1 WO 2021223026A1 CA 2021050628 W CA2021050628 W CA 2021050628W WO 2021223026 A1 WO2021223026 A1 WO 2021223026A1
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peptide
amino acid
acid sequence
sequence
seq
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PCT/CA2021/050628
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English (en)
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Yu Tian Wang
Jack Wuyang Jin
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University Of British Columbia
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22

Definitions

  • the present disclosure relates generally to EZH1/2 knockdown peptides, methods and uses thereof, including the potential application of such peptides in treating diseases such as cancer.
  • Enhancer of zeste homolog 2 is a histone-lysine N-methyltransferase enzyme that methylates lysine 27 of histone H3 (H3K27) to promote transcriptional silencing. It is a part of the Polycomb Repressive Complex 2 (PRC2), a chromatin-modifying complex involved in maintaining transcriptional repression. PRC2 contains four essential subunits in mammals: embryonic ectoderm development (EED), suppressor of zeste 12 homolog (SUZ12), retinoblastoma-binding protein 4/7 (RBBP4/7), and either EZH2 or its homolog EZH1. While EZH1 is more abundant in non-proliferative adult organs, EZH2 expression is tightly associated with proliferation.
  • EZH2 Aberrant expression of the EZH2 gene has been linked with many types of human diseases, including cancer, rare diseases and neurodegeneration.
  • EZH2 downregulates expression of tumor suppressor genes and upregulates oncogenes, promoting cancer cell survival, proliferation, and epithelial-to-mesenchymal transition and invasion.
  • EZH2 gain-of-function mutations and overexpression have been identified in more than 10 different types of cancer, such as liver cancer, prostate cancer and lung cancer.
  • EZH1 mutations have also been observed in thyroid tumors, although its role in various cancers is not believed to be as important as that of EZH2.
  • a knockdown peptide comprising: (a) a cell membrane penetration sequence; (b) an EZH2 binding sequence; and (c) a KFERQ-like chaperone-mediated autophagy (CMA) targeting sequence.
  • the binding sequence comprises an amino acid sequence having at least about 90% identity with the amino acid sequence of SEQ ID NO:3.
  • the binding sequence comprises an amino acid sequence having at least about 95% identity with the amino acid sequence of SEQ ID NO:3.
  • a peptide, or a pharmaceutically acceptable salt or derivative thereof comprising an amino acid sequence having at least about 90% identity with the amino acid sequence of SEQ ID NO:7.
  • a peptide, or a pharmaceutically acceptable salt or derivative thereof comprising an amino acid sequence having at least about 95% identity with the amino acid sequence of SEQ ID NO:7.
  • the EZH2 binding sequence is also an EZH1 binding sequence.
  • the peptide is prepared by chemical synthesis.
  • a peptide for use in binding EZH2 and transporting the peptide-EZH2 protein complex to the lysosome for degradation is provided.
  • the intracellular expression level of EZH2 is reduced.
  • the intracellular expression level of EZH1 is reduced.
  • the delivery of the peptide to the cell is effected in vitro.
  • the delivery of the peptide to the cell is effected ex vivo.
  • the delivery of the peptide to the cell is effected in vivo.
  • the binding sequence comprises an amino acid sequence having at least about 95% identity with the amino acid sequence of SEQ ID NO:3.
  • the binding sequence comprises the amino acid sequence of SEQ ID NO:3.
  • the cell membrane penetration sequence comprises the amino acid sequence of SEQ ID NO:4.
  • the CMA-targeting sequence comprises the amino acid sequence of SEQ ID NO:5.
  • the peptide comprises an amino acid sequence having at least about 90% identity with the amino acid sequence of SEQ ID NO:7.
  • the peptide comprises an amino acid sequence having at least about 95% identity with the amino acid sequence of SEQ ID NO:7.
  • the subject is a human.
  • the disease or pathological condition is associated with mutation and/or overexpression of EZH2.
  • the disease or pathological condition is associated with mutation and/or overexpression of EZH1.
  • the disease or pathological condition is cancer.
  • the cancer is liver cancer.
  • the administering of the effective amount of the peptide is by systemic administration.
  • the binding sequence comprises an amino acid sequence having at least about 90% identity with the amino acid sequence of SEQ ID NO:3.
  • the binding sequence comprises an amino acid sequence having at least about 95% identity with the amino acid sequence of SEQ ID NO:3.
  • the binding sequence comprises the amino acid sequence of SEQ ID NO:3.
  • the cell membrane penetration sequence comprises the amino acid sequence of SEQ ID NO:4.
  • the CMA-targeting sequence comprises the amino acid sequence of SEQ ID NO:5.
  • the peptide comprises the amino acid sequence of SEQ ID NO:7.
  • a pharmaceutical composition comprising: an effective amount of a knockdown peptide, the peptide comprising: a cell membrane penetration sequence; an EZH2 binding sequence; and a KFERQ-like CMA targeting sequence, or a pharmaceutically acceptable salt or derivative thereof; and at least one pharmaceutically acceptable excipient or adjuvant.
  • Figure la referred to also herein as Figure 1(a), is a schematic illustration of a knockdown peptide design
  • Figure lb shows a number of immunoblotting images and a normalized optical density graph
  • Figure 2b shows a number of immunoblotting images and a normalized optical density graph
  • Figure 2c shows a number of immunoblotting images and a normalized optical density graph
  • Figure 3a shows a number of immunoblotting images
  • Figure 3b shows a normalized optical density graph
  • Figure 3c shows a normalized optical density graph
  • Figure 3d shows a number of immunoblotting images and a normalized optical density graph
  • Figure 3e shows a number of immunoblotting images and a normalized optical density graph
  • the present description provides, in one aspect, a membrane-permeable peptide which binds to EZH2 and targets it for degradation via the lysosome.
  • a peptide as described herein comprising the amino acid sequence of SEQ ID NO: 3 (KQLARRKWWFNY) as a binding sequence was found to provide potent and effective knockdown of EZH2 in cultured cells and in free-moving animals. In addition, such a peptide was also surprisingly found to effectively knock down EZH1 at least in cultured cells.
  • Exemplary EZH2 binding sequences as described herein were derived from the histone H3 protein and designed to mimic the H3K27 methylation site. Both EZH1 and EZH2 can bind to the H3 protein and methylate the H3K27 site.
  • a peptide according to the present description may effectively knock down EZH2 in liver cells in a selective fashion following systemic administration, thus offering the potential for targeted therapeutic application in diseases such as liver cancer.
  • EZH2 overexpression has been identified in liver cancer and inhibition of EZH2 could induce natural killer cell-mediated eradication of hepatocellular carcinoma cells. Selective delivery of PP-SIM2 to the liver may significantly reduce side effects and toxicity during cancer treatment.
  • EZH2 is an unstable protein in the cell with a relatively high turnover rate (half- life is around 2 hours)
  • a single treatment of a peptide according to the present description was able to reduce the level of endogenous EZH2 protein in cultured LNCaP cells for more than 8 hours. Therefore, depending on the dose, twice a day treatment may be sufficient to maintain a low level of EZH2 protein in the cell.
  • the present description relates to a knockdown peptide comprising: 1) a cell membrane penetration sequence; 2) an EZH2 binding sequence; and 3) a KFERQ-like chaperone- mediated autophagy (CMA) targeting sequence.
  • the EZH2 binding sequence is also an EZH1 binding sequence.
  • the binding sequence may comprise an amino acid sequence having at least about 90%, or 95%, or 99%, or even 100% identity with the amino acid sequence of SEQ ID NO: 3 (KQLARRKWWFNY). In one aspect, the binding sequence may consist of the amino acid sequence of SEQ ID NO: 3.
  • the peptide may comprise an amino acid sequence having at least about 90%, or 95%, or 99%, or even 100% identity with the amino acid sequence of SEQ ID NO: 7 ( Y GRKKRRQRRRKQL ARRKWWFNYKFERQKILDQRFFE) (“PP-SIM2”).
  • the peptide may comprise the amino acid sequence of SEQ ID NO:7, or a pharmaceutically acceptable salt or derivative thereof.
  • the peptide may be used to bind EZH2 and transport the peptide-EZH2 protein complex to the lysosome for degradation.
  • the present description relates to a method of reducing the intracellular expression level of EZH2 and/or EZH1, comprising delivering to a cell an effective amount of a knockdown peptide comprising: 1) a cell membrane penetration sequence; 2) an EZH2 binding sequence; and 3) a KFERQ-like CMA targeting sequence.
  • the delivery of the peptide to the cell may be in vitro , or ex vivo, or in vivo.
  • the present description relates to a method of treating a disease or pathological condition comprising administering an effective amount of a knockdown peptide comprising: 1) a cell membrane penetration sequence; 2) an EZH2 binding sequence; and 3) a KFERQ-like CMA targeting sequence, to a subject in need thereof.
  • the subject may be a human.
  • the disease or pathological condition may be associated with mutation and/or overexpression of EZH2.
  • the disease or pathological condition may be associated with mutation and/or overexpression of EZH1.
  • the cancer may be liver cancer, prostate cancer, lung cancer, or thyroid cancer.
  • the peptide may be administered systemically, e.g., intravenously.
  • the present description relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a knockdown peptide, the peptide comprising: 1) a cell membrane penetration sequence; 2) an EZH2 binding sequence; and 3) a KFERQ-like CMA targeting sequence, or a pharmaceutically acceptable salt or derivative thereof; and at least one pharmaceutically acceptable excipient or adjuvant.
  • the knockdown peptide may have at least about 90%, or 95%, or 99%, or even 100% identity with the amino acid sequence of SEQ ID NO:7.
  • amino acids comprising a peptide or polypeptide described herein may also be modified either by natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in a peptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It is understood that the same type of modification may be present in the same or varying degrees at several sites in a given peptide.
  • Amino acids are molecules containing an amine group, a carboxylic acid group and a side chain that varies between different amino acids. An amino acid may be in its natural form or it may be a synthetic amino acid.
  • Acidic amino acids have a net negative charge at a neutral pH.
  • acidic amino acids include aspartate and glutamate.
  • Basic amino acids have a net positive charge at a neutral pH.
  • basic amino acids include arginine, lysine and histidine.
  • Aromatic amino acids are generally nonpolar, and may participate in hydrophobic interactions. Examples of aromatic amino acids include phenylalanine, tyrosine and tryptophan. Tyrosine may also participate in hydrogen bonding through the hydroxyl group on the aromatic side chain.
  • Neutral, aliphatic amino acids are generally nonpolar and hydrophobic. Examples of neutral amino acids include alanine, valine, leucine, isoleucine and methionine.
  • An amino acid may be described by more than one descriptive category.
  • Amino acids comprising the peptides described herein will be understood to be in the L- or D- configuration. Amino acids described herein may be modified by methylation, amidation, acetylation or substitution with other chemical groups which may change the circulating half-life of the peptide without adversely affecting their biological activity.
  • sequence identity when considering the degree of identity with SEQ ID NOs: 3 or 7, it is intended that the equivalent number of amino acids be compared to SEQ ID NOs: 3 or 7, respectively. Additional sequences (i.e. other than those corresponding to the 12 or 37 amino acids of SEQ ID NOs: 3 or 7, respectively), are not intended to be considered when determining the degree of identity with SEQ ID NOs: 3 or 7.
  • the sequence identity of a given sequence may be calculated over the length of the reference sequence (i.e. SEQ ID NOs: 3 or 7).
  • aliphatic fatty acids, alcohols and amines may be used, such as caprylic acid, capric acid, lauric acid, myristic acid and myristyl alcohol, palmitic acid, palmitoleic acid, stearic acid and stearyl amine, oleic acid, linoleic acid, docosahexaenoic acid, etc.
  • Preferred are unbranched, naturally occurring fatty acids between 14- 22 carbon atoms in length.
  • Other lipophilic molecules include glyceryl lipids and sterols, such as cholesterol.
  • the lipophilic groups may be reacted with the appropriate functional group on the peptide in accordance with conventional methods, frequently during the synthesis on a support, depending on the site of attachment of the oligopeptide to the support.
  • Lipid attachment is useful, for example, where peptides may be introduced into the lumen of a liposome, optionally along with other therapeutic agents, for administering the peptides and optionally agents into a host.
  • the subject peptides may also be modified by attachment to other compounds for the purposes of incorporation into carrier molecules, changing peptide bioavailability, extending or shortening half-life, controlling distribution to various tissues or the blood stream, diminishing or enhancing binding to blood components, and the like.
  • the peptides herein may comprise a delivery and targeting (dat) moiety.
  • delivery and targeting (dat) moiety as used herein is meant to encompass any moiety that assists in delivering and/or targeting the peptides described herein to a target cell or tissue or within a target cell or within the cells of a target tissue.
  • the dat moiety may be a cell membrane penetrating sequence.
  • a dat moiety may “assist” in delivery and/or targeting by virtue of promoting the biological efficacy of the peptides described herein.
  • Moieties that enable delivery or targeting of bioactive molecules into cells in a suitable manner so as to provide an effective amount, such as a pharmacologically effective amount, are known in the art.
  • the delivery and targeting (dat) moiety may comprise, or may be selected from, one or more of: receptor ligands, protein transduction domains, micelles, liposomes, lipid particles, viral vectors, peptide carriers, protein fragments, or antibodies.
  • the protein transduction domain may be the cell-membrane transduction domain ofHIV-1 Tat (Demarchi etal. (1996) J Virol. 70: 4427- 4437). Other examples and related details of such protein transduction domains are described and known to those skilled in the art.
  • compositions described herein may be administered to a subject having a disease or condition, such as (but not limited to) cancer, which may be, for example, liver cancer, prostate cancer, lung cancer, or thyroid cancer.
  • a disease or condition such as (but not limited to) cancer
  • the composition described herein may be administered to a subject in an amount sufficient to cure or at least partially arrest or reduce at least one manifestation of the disease or condition and/or its complications or to help alleviate at least one symptom associated therewith.
  • Such an amount is defined as a “therapeutically effective amount” or an “effective amount”. Amounts effective for this use will depend upon the severity of the disease or condition, the intended use (treatment, cure, prophylactic, alleviation of symptoms, etc.) and the general state of the subject’s health.
  • compositions may be administered depending on the dosage and frequency as required and tolerated by the patient.
  • a composition generally would provide a sufficient quantity of the active peptide or peptides described herein to effectively treat (for example, to at least ameliorate one or more symptoms) in the subject.
  • concentration(s) of peptide described herein can vary widely, and may be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs. Concentrations, however, will typically be selected to provide dosages ranging from about 0.01 or 1 mg/kg/day to about 50 mg/kg/day and sometimes higher. It will be appreciated that such dosages may be varied to optimize a therapeutic regimen in a particular subject or group of subjects.
  • Additional active therapeutic ingredients may be administered to the subject along with or prior to the primary active agent, e.g., the exemplary peptides described herein.
  • the exemplary peptide may be co-administered with one or more other therapeutically active agents to enhance the therapeutic effect on the target cell or tissue by delivering another compound or compounds with a similar or complementary activity.
  • Peptides may be prepared in a number of ways. Chemical synthesis of peptides is well known in the art. Solid phase synthesis is commonly used and various commercial synthetic apparatuses are available, for example automated synthesizers by Applied Biosystems Inc., Foster City, Calif.; Beckman; etc. Solution phase synthetic methods may also be used, particularly for large-scale productions. Recombinant DNA, genetic and molecular engineering techniques are also known in the art.
  • Peptides may also be present in the form of a salt, generally in a salt form which is pharmaceutically acceptable. These include inorganic salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and the like. Various organic salts of the peptide may also be made with, including, but not limited to, acetic acid, propionic acid, pyruvic acid, maleic acid, succinic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, salicylic acid, etc.
  • Figures 1(a) and 1(b) Screening and selecting a potent EZH2 knockdown peptide.
  • Figure 1(a) schematic illustration of knockdown peptide design. All peptide candidates (PP-SIM1, PP-SIM2, PP-SIM3, and PP-SIM4) were composed of three parts: 1) a membrane-permeable Tat sequence; 2) a potential EZH2 protein binding sequence; 3) a chaperone-mediated autophagy lysosomal degradation signal.
  • Naive C57BL/6 mice received an i.p. injection of either saline control or 10 mg/kg PP-SIM2 and were sacrificed 4 hours later. Liver, lung, kidney and prostate were taken out for immunoblotting analysis.
  • Tat cell penetration sequence (YGRKKRRQRRR) is shown in bold and the KFERQ-like chaperone- mediated autophagy targeting motifs are underlined.
  • Buffers and media Phosphate buffered saline (PBS, pH 7.4) contains 137 mMNaCl, 2.7 mM KC1, 8.1 mM Na2HP04, and 1.76 mM KH2P04.
  • Cell lysis buffer contained 0.5% Triton X- 100, 0.5% deoxy cholic acid, and 1 c protease and phosphatase inhibitor cocktail (Thermo Scientific, 78442) in sterile PBS.
  • 4x sample buffer contains 50% Glycerol, 125 mM pH 6.8 Tris-HCl, 4% SDS, 0.08% bromophenol blue, and 5% b-mercaptoethanol.
  • the neuron culture medium contained 2% B-27 supplement (Invitrogen, 17504-044) and 0.5 mM GlutaMax supplement (Invitrogen, 35050-061) in Neurobasal Medium (Invitrogen, 21103-049).
  • Rat primary neuron cultures were prepared from embryos of pregnant Sprague-Dawley rats (E18). Briefly, the cortical tissue was isolated into ice cold HBSS (Invitrogen, 14170-112) and then digested with 0.25% trypsin-EDTA at 37°C for 30 min. After washing with warm DMEM (supplemented with 10% FBS) three times, neurons were suspended in the neuron culture medium and dissociated by trituration using varying sizes of pipettes. Neurons were then centrifuged, and the pellet was re-suspended in the culture medium, washed twice with the culture medium, and plated on the poly-D-lysine-coated plates.
  • DMEM supplied with 10% FBS
  • Neuron cultures were maintained in the 37°C incubator with 95% 02 and 5% C02. The morning after culturing, 2/3 of the neuron culture medium was replaced with fresh neuron culture medium. Medium was then replaced every 3-4 days. Rat primary cortical neuron cultures were used 14 days in vitro. [0116] Immunoblotting: Animal tissues or cultured cells were lysed on ice in the lysis buffer and then the solution was centrifuged at 14,000 rpm for 10 min at 4°C. Next, the supernatant was collected and protein concentrations were determined using a BCA protein assay kit (Thermo Scientific, 23227).
  • Equal amounts of protein samples were mixed with 4x sample buffer, boiled at 100°C for 5 min, and separated on 10% sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Proteins were then transferred to Immobilon-PTM polyvinylidene fluoride (PVDF) membranes (Bio-Rad, 162-0177). The membranes were blocked with 5% non fat milk in Tris-buffered saline containing 0.1% Tween-20 (TBST) for 1 hr at room temperature, and then incubated overnight at 4°C with primary antibody. After washing 3 x 5 min in TBST, membranes were incubated with horseradish peroxidase-conjugated secondary antibody for one hour at room temperature.
  • PVDF polyvinylidene fluoride
  • LNCaP prostate cancer cells were treated with different doses of the PP-SIM2 peptide (5 mM, 25 mM and 50 pM) and harvested 4 hours after treatment. There was a significant reduction of EZH2 protein levels after 5 pM and 25 pM PP-SIM2 treatment (Fig. 2a). Surprisingly, a reduction of the b-actin protein level was observed in the 50 pM PP-SIM2 group (Fig.2a), possibly due to high dose treatment-induced acute stress to these sensitive cells. The loss of the b-actin protein is unlikely due to cell apoptosis, because apoptosis usually occurs 12-24 hours after treatment.
  • LNCaP cells were treated with 20 mM PP-SIM2 peptide and harvested at different time points (2 h, 4 h, 8 h and 24 h).
  • a transient, time-dependent reduction of EZH2 was observed in cultured cells (Fig. 2b).
  • a significant EZH2 knockdown was observed 2-4 hours after peptide treatment and a partial, insignificant reduction of the EZH2 protein level was observed 8 hours after peptide treatment.
  • the EZH2 protein level fully recovered at 24 hours (Fig. 2b).
  • the EZH1 protein was found to be weakly expressed in LNCaP prostate cancer cells. Since mature brain neurons have a high expression level of the EZH1 protein, rat primary cortical neurons were treated with 20 mM PP-SIM2 for 4 hours to test the specificity of PP-SIM2. A significant knockdown of EZH1 was observed in primary cortical neurons (Fig. 2c) and the level of EZH1 reduction was similar to that of EZH2 in LNCaP prostate cancer cells (Fig. 2a-b), suggesting that PP-SIM2 recognizes both EZH1 and EZH2.

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Abstract

La présente invention concerne un peptide inactivé qui comprend : (a) Une séquence de pénétration de membrane cellulaire ; (b) une séquence de liaison à EZH2 ; et (c) une séquence de ciblage d'autophagie à médiation par un chaperon (CMA) de type KFERQ. Un procédé de réduction du niveau d'expression intracellulaire d'au moins l'un de l'EZH1 et de l'EZH2 comprend l'administration d'une quantité efficace d'un peptide inactivé à une cellule ; le peptide comprenant : (a) Une séquence de pénétration de membrane cellulaire ; (b) une séquence de liaison d'EZH2 ; et (c) une séquence de ciblage de CMA de type KFERQ. La présente invention concerne également une composition pharmaceutique qui comprend : (a) Une quantité efficace d'un peptide inactivé, le peptide comprenant : i) une séquence de pénétration de membrane cellulaire ; ii) une séquence de liaison d'EZH2 ; et iii) une séquence de ciblage de CMA de type KFERQ, ou un sel ou dérivé pharmaceutiquement acceptable de celle-ci ; et (b) au moins un excipient ou un adjuvant pharmaceutiquement acceptable.
PCT/CA2021/050628 2020-05-06 2021-05-05 Peptides à inactivation ezh1/2, procédés et utilisations de ceux-ci WO2021223026A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2885894A1 (fr) * 2012-09-27 2014-04-03 University Of British Columbia Inactivation de proteine dirigee par un peptide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2885894A1 (fr) * 2012-09-27 2014-04-03 University Of British Columbia Inactivation de proteine dirigee par un peptide

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEN XI: "Design and optimization of small peptides that regulate the balance of synaptic excitation and inhibition", UBC LIBRARY-THESIS, UNIVERSITY OF BRITISH COLUMBIA, 1 April 2017 (2017-04-01), XP055870579, Retrieved from the Internet <URL:https://open.library.ubc.ca/media/download/pdf/24/1.0347285/4> [retrieved on 20211208], DOI: 10.14288/1.0347285 *
FAN ET AL.: "Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation", NATURE NEUROSCIENCE, vol. 17, no. 3, March 2014 (2014-03-01), pages 471 - 480, XP055256851, ISSN: 1546-1726, DOI: 10.1038/nn.3637 *
SMADBECK JAMES, PETERSON MEGHAN B., ZEE BARRY M., GARAPATY SHIVANI, MAGO AASHNA, LEE CHRISTINA, GIANNIS ATHANASSIOS, TROJER PATRIC: "De Novo Peptide Design and Experimental Validation of Histone Methyltransferase Inhibitors", PLOS ONE, vol. 9, no. 2, e90095, 28 February 2014 (2014-02-28), XP055870574, DOI: 10.1371/journal.pone.0090095 *
YAMAGISHI MAKOTO, UCHIMARU KAORU: "Targeting EZH2 in cancer therapy", CURRENT OPINION IN ONCOLOGY, LIPPINCOTT WILLIAMS & WILKINS, LTD., GB, vol. 29, no. 5, 1 September 2017 (2017-09-01), GB , pages 375 - 381, XP055870570, ISSN: 1040-8746, DOI: 10.1097/CCO.0000000000000390 *

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