WO2024003227A1 - Peptide artificiel présentant un effet inhibiteur de la pkmt - Google Patents

Peptide artificiel présentant un effet inhibiteur de la pkmt Download PDF

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Publication number
WO2024003227A1
WO2024003227A1 PCT/EP2023/067788 EP2023067788W WO2024003227A1 WO 2024003227 A1 WO2024003227 A1 WO 2024003227A1 EP 2023067788 W EP2023067788 W EP 2023067788W WO 2024003227 A1 WO2024003227 A1 WO 2024003227A1
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peptide
pkmt
amino acid
peptides
loop structure
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PCT/EP2023/067788
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German (de)
English (en)
Inventor
Albert Jeltsch
Philipp SCHNEE
Sara WEIRICH
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Universität Stuttgart
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Publication of WO2024003227A1 publication Critical patent/WO2024003227A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
    • C12N9/1007—Methyltransferases (general) (2.1.1.)
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to an artificial peptide with a strong binding affinity to a protein lysine methyltransferase, a method for producing the peptide and uses of the peptide.
  • PKMT Protein lysine methyltransferases
  • PKMTs The incorporation of the methyl group by PKMTs is accomplished using a cofactor that provides an activated methyl group.
  • This cofactor is called S-Adenosyl-L-Methionine (SAM) and binds together with the histone peptide in the active site of the PKMT (Fig. 1) [Boriack-Sjodin & Swinger, 2015].
  • SAM S-Adenosyl-L-Methionine
  • Fig. 1 [Boriack-Sjodin & Swinger, 2015].
  • the transferred methyl group then acts as a signal and sets a Cascade in motion, which leads to the restructuring of the chromatin [Ailis & Jenuwein, 2016], This restructuring decides which genes are switched on and which are not [Ailis & Jenuwein, 2016], so PKMTs play a central role in gene regulation.
  • SAM inhibitors for PKMTs is problematic in terms of the specificity of the molecules because other methyltransferase enzyme families, such as DNA methyltransferases, RNA methyltransferases or protein arginine methyltransferases, also use SAM as a donor for methyl groups. SAM derivatives can therefore also interact with them and influence their activity. In defined forms of cancer, the activity of specific PKMTs is always altered and these must be specifically regulated [Kudithipudi & Jeltsch, 2014; Copeland et al. 2013], Specific PKMT inhibitors would also be valuable reagents in research that allow the biological function of a specific PKMT to be examined in more detail.
  • the task is therefore to meet an urgent need for inhibitors that specifically inhibit certain PKMTs.
  • a peptide according to claim 8 a use according to claim 14 and one Use solved according to claim 15.
  • Further advantageous embodiments and refinements of the invention result from the subclaims, the illustrations and the exemplary embodiments.
  • the embodiments of the invention can be combined in an advantageous manner.
  • a first aspect of the invention relates to a method for producing an artificial peptide with a length in the range of 10 to 20 amino acids with an amino acid sequence derived from a portion of a substrate for a protein lysine methyltransferase (PKMT), wherein the peptide has a strong Has binding affinity to a PKMT, with the steps:
  • a peptide array with first peptides with a length of 10 to 20 amino acids with amino acid sequences derived from a section of the substrate for a PKMT is provided, the first peptides having different amino acid sequence variants and each having at least one basic one to be methylated amino acid, and methylation of the peptides by a PKMT,
  • At least one first peptide is identified which has a particularly strong methylation ability compared to known substrate peptides of a specific protein lysine methyltransferase,
  • a third substep S1.3 design and manufacture of derived peptides, the amino acid sequence of which should enable the formation of a loop structure and a basic amino acid to be methylated should be positioned in the center of the loop structure,
  • a second sub-step 2.2 design and manufacture of derived peptides based on the data obtained in the previous design process, the amino acid sequence of which should enable the formation of a loop structure, with a basic amino acid to be methylated being positioned in the center of the loop structure,
  • - derived peptides are produced on the basis of the data obtained in the previous design process, the amino acid sequence of which should enable the formation of a loop structure, with a basic amino acid to be methylated being positioned in the center of the loop structure, and the inhibition of PKMT by the peptides is then examined, to identify at least one peptide that exhibits particularly strong inhibition of PKMT, whereby the third design process can be repeated if necessary.
  • the steps are also known as the design process, which are divided into sub-steps.
  • an initial design process artificial substrate peptides are identified in several cycles that are methylated by the PKMT at the highest possible rate.
  • artificial substrate peptides are identified in several cycles that have the largest possible bind to the PKMT via affinity.
  • peptides are then identified that inhibit PKMT with the highest possible efficiency.
  • the peptides from the second design process are produced with a length in the range of 10 to 20 amino acids, which are based on the amino acid sequence of the identified substrate peptide, the amino acid sequence of the derived peptides being intended to enable the formation of a loop structure and a basic amino acid to be methylated in the center of the Loop structure should be positioned.
  • the inhibition of PKMT by these peptides is then examined in order to identify at least one peptide that exhibits particularly strong inhibition.
  • the process is started with first peptides, from which the derived peptides are derived, from which a new peptide is in turn identified. This process can be repeated several times and gradually optimizes the methylation, binding and inhibitory effects of the derived peptides.
  • the final, best interacting and inhibitory peptides are identical to the artificial peptide according to the invention.
  • the method according to the invention can be used to identify at least one peptide that inhibits the activity of a PKMT.
  • loop structure refers to a conformation of a protein or, in the sense of the invention, a peptide, which fits particularly well to the binding pocket of the enzyme in the biochemical sense of the key-lock principle.
  • the loop structure is in particular a structural element in which a folding-back loop (“loop region”) is stabilized by interactions of the amino acids before and after the loop region (“stem region”).
  • Loop region a folding-back loop
  • stem region a folding-back loop
  • Positioning the basic amino acid to be methylated in the center of the loop structure means that the basic amino acid to be methylated is positioned in the loop area.
  • An advantageous form of a loop structure refers to a U-shaped structure of the peptide with a short end-to-end distance. A hairpin-like loop of the peptide is formed. Other conformations are also possible.
  • a histone protein is chosen as the substrate for a PKMT.
  • said basic amino acid is a proteinogenic, non-proteinogenic or modified amino acid.
  • the basic amino acid is lysine.
  • the strong binding affinity of the peptide to a PKMT exceeds the binding affinity of a natural histone protein.
  • strong and “particularly strong” in relation to the binding of peptides to a PKMT, which can be illustrated by a degree of methylation, are to be seen relative to other peptides.
  • a strong bond is several times higher than that of conventional peptides.
  • Very strong bonds are several times higher than those of strongly binding peptides.
  • a preferred embodiment of the method is advantageous in which a PKMT is chosen that is correlated with a disease in terms of its enzyme activity. This enables the design of a peptide that is suitable for treating a corresponding disease.
  • a PKMT is chosen in the method that is correlated with a cancer disease in terms of its enzyme activity. This can advantageously provide a peptide that is suitable for treating a cancer disease.
  • a PKMT is selected from a group comprising NSD2, SETD2, EZH2 and DOT1L.
  • NSD2, SETD2, EZH2 and DOT1L For this PKMT has been shown to be correlated with the development of certain types of cancer. It is therefore particularly advantageous if a peptide for inhibiting this PKMT is provided that is suitable for treating corresponding types of cancer.
  • a second aspect of the invention relates to an artificial peptide produced by the method according to the invention with a length in the range of 10 to 20 amino acids with an amino acid sequence derived from a section of a substrate for a protein lysine methyltransferase (PKMT), the peptide being a has strong binding affinity to a PKMT.
  • the special amino acid sequence enables the formation of a loop structure.
  • a basic amino acid to be methylated is positioned at the center of the loop structure.
  • the peptide has an inhibitory effect on the enzyme activity of protein lysine methyltransferase.
  • the peptide according to the invention is advantageous because it binds a specific PKMT in a highly specific manner and thus reduces the activity of the PKMT.
  • the initial binding occurs in a loop conformation in which the peptide according to the invention can bind to the PKMT more quickly and efficiently.
  • the final binding in the active site of the PKMT can occur in a loop conformation or in an extended form after unfolding.
  • the inhibitory effect of the peptides occurs through a competitive inhibition of the binding of the histone protein to the protein lysine methyltransferase. This selectively prevents the binding of histones (i.e. the real substrates) to the corresponding PKMT.
  • the peptide according to the invention is advantageously specific compared to conventional approaches because it does not address the SAM binding site of the enzyme and therefore does not inhibit other methyltransferases or other PKMTs. Furthermore, the peptide according to the invention can be used to examine the biological function of a specific PKMT.
  • a peptide with a loop structure of PKMT methylates more efficiently than the corresponding linear peptide and it associates with the PKMT more quickly and efficiently. It is therefore advantageous to provide a loop conformation in the design of the peptide according to the invention. Further work showed that the formation of a loop structure allows for faster binding to a desired PKMT (see Figure 6 for illustration).
  • the loop structure can be held together in particular by a chemical bond selected from the group of covalent bonds, hydrogen bonds or hydrophobic interactions.
  • a covalent bond that is stable and can be achieved via a reaction of functional groups that can be incorporated during the chemical synthesis of the peptides is particularly advantageous.
  • the formation of a disulfide bridge across two cysteine residues is suitable.
  • Embodiments of the peptide according to the invention are therefore advantageous, the amino acid sequence of which each has at least two amino acids which can form a disulfide bridge or another chemical bond that stabilizes the loop structure.
  • the substrate for a PKMT is a histone protein.
  • said basic amino acid is a proteinogenic, non-proteinogenic or modified proteinogenic amino acid.
  • Proteinogenic are amino acids that occur naturally in proteins.
  • Non-proteinogenic are amino acids (i.e. acids with an amino group on Ca) that occur naturally, but not as building blocks of proteins.
  • Modified are proteinogenic amino acids that have an artificial or natural chemical modification.
  • Lysine, arginine or histidine can be used as proteinogenic basic amino acids.
  • Ornithine or meta-amino-phenylalanine, for example, can be used as non-proteinogenic basic amino acids.
  • Possible modified proteinogenic basic amino acids are, for example, methylated lysine, methylated arginine or methylated histidine.
  • the basic amino acid is preferably a lysine. However, other basic amino acids are also possible and also preferred, especially ornithine.
  • the peptide is specific for binding by a specific PKMT.
  • the final binding can be in a loop shape or a stretched shape.
  • the peptide is specific, for example, for SETD2 (SET-domain containing protein 2, also known as KMT3A). It was shown that this enzyme interacts particularly efficiently with corresponding peptides.
  • SETD2 SET-domain containing protein 2, also known as KMT3A.
  • KMT3A SET-domain containing protein 2, also known as KMT3A
  • the specific protein lysine methyltransferase is correlated with a disease in terms of its enzyme activity. It can be assumed that many diseases are correlated with hyperactivity of PKMT.
  • the specific PKMT is correlated with cancer, neurological disorders, brain diseases, inflammatory disorders, metabolic diseases and diseases of the cardiovascular system.
  • a therapy is tailored to a specific type of disease, in particular a specific tumor type and even a specific patient. This enables, for example, personalized cancer therapy, which could give the invention a place alongside already established methods such as antibody or CAR T-cell therapy.
  • the strong binding affinity of the peptide to a PKMT exceeds the binding affinity of a natural histone protein.
  • the amino acid sequence of the peptide according to the invention is derived from a known PKMT substrate, for example in the case of SETD2 from the N-terminal tail region of the histone protein H3.
  • the binding of PKMTs to histone proteins occurs by binding the enzyme to the freely accessible, so-called “histone tail”.
  • This tail represents the N-terminal end of the histone protein, consists of a specific sequence of around 20 to 40 amino acids and contains characteristic lysine residues at certain positions.
  • other residues within the histone proteins e.g. H3K79
  • non-histone proteins are also methylated by PKMTs. These methylation events also have important biological functions and are therefore also potential targets for PKMT inhibitors.
  • a third aspect of the invention relates to a use of a peptide according to the invention for inhibiting the enzyme activity of a specific protein lysine methyltransferase.
  • suitable PKMTs are NSD2, SETD2, EZH2 and DOT1 L. This use relates in particular to a medical use for treating the diseases mentioned below, especially cancer diseases.
  • a fourth aspect of the invention relates to a use of a peptide for inhibiting the enzyme activity of a specific protein lysine methyltransferase, using a peptide obtained in step S1, S2 or S3 of the method according to the invention.
  • All peptides that are obtained and tested in the design process in step S1, S2 or S3 of the method according to the invention are possible. This includes not only the final peptide obtained, but also the peptides obtained in the intermediate steps. The latter are referred to as substrates or, if they already bind PKMT very effectively, as supersubstrates. These peptides can also be used as PKMT inhibitors.
  • substrate peptides that can already be shown to have a strong inhibitory effect are advantageous for use in the further design process to generate even more effective inhibitors.
  • a pharmaceutical composition which contains at least one peptide according to the invention with at least one pharmaceutically acceptable carrier substance, mesopore nanoparticles, an antifreeze medium, a lyoprotectant, an excipient and / or a diluent.
  • a further aspect of the invention relates to a peptide according to the invention for use as a medication.
  • a drug is possible against any disease in which the peptide is effective as an inhibitor of a PKMT that is involved in the cause of the disease.
  • the drug can be used particularly advantageously in cancer therapy, since treating cancer by inhibiting PKMT using other strategies is already known.
  • a drug that can be used in the treatment of neurological disorders, brain diseases, inflammatory disorders, metabolic diseases and diseases of the cardiovascular system is also possible.
  • a further aspect of the invention relates to a peptide according to the invention for use in the treatment of cancer, in particular a cancer disease in which defective methylation of histone proteins by a protein lysine methyltransferase occurs.
  • the peptide according to the invention is preferably used for the treatment of cancer of the liver, cancer of the pancreas, cancer of the prostate, breast cancer, another solid tumor or a cancer of the hematopoietic system.
  • a peptide according to the invention In order to use a peptide according to the invention, it must be provided in a suitable form.
  • the peptide is used to produce a formulation for oral, intravenous, topical, intranasal, intraperitoneal and/or subcutaneous administration and/or inhalation and/or another injectable form.
  • a method for the prophylaxis and/or treatment of cancer in a subject wherein the subject is administered a peptide according to the invention or a corresponding pharmaceutical composition becomes.
  • the subject is a mammal and, in a special embodiment, a human.
  • Figure 1 shows a schematic representation of a transfer of a methyl group from SAM to the N-terminal end of a histone protein by the PKMT.
  • Figure 2 shows a schematic representation of a peptide according to the invention bound to a PKMT, which prevents the docking of the N-terminal end of a histone protein.
  • Figure 3 shows a flow diagram of an embodiment of a method according to the invention.
  • Figure 4 shows an autoradiogram of a spot array for identifying a peptide according to the invention in design cycles.
  • Figure 5 shows an autoradiogram of a spot array to demonstrate the specificity of substrates for certain PKMT.
  • Figure 6 Data from a FRET experiment to demonstrate a loop conformation that the peptide according to the invention adopts in solution.
  • Figure 8 shows an autoradiogram to demonstrate the inhibitory effect of certain peptides on a PKMT.
  • the methylation of a histone protein 1 is shown schematically in FIG.
  • the methyl group 3 to be transferred is provided by a cofactor called S-adenosyl-L-methionine (SAM) 4.
  • SAM 4 is delivered together with the Histone protein 1 bound in the active site of PKMT 2.
  • the methyl group 3 is transferred to a region of histone protein 1.
  • the transferred methyl group 3 acts as a signal and sets in motion a cascade that leads to a restructuring of the chromatin in which genomic DNA and histones are arranged together. This restructuring determines which genes can be switched on and which cannot.
  • a protein lysine methyltransferase (PKMT) 2 has an active site for the methylation of regions of histone proteins, in which the cofactor SAM 4 and the peptide to be methylated 10c bind.
  • An artificial peptide 10 is provided which is present in solution in a looped 10b or stretched conformation 10a.
  • the artificial peptide associates with a specific PKMT preferentially in a loop conformation 10b and finally binds in the active site region of the PKMT in a loop or stretched form 10c.
  • the bound peptide 10c binds more strongly than histone protein 1 and thereby prevents it from binding to PKMT 2. This means that the histone protein cannot be methylated.
  • the method is divided into three design processes.
  • a first design process S1 artificial PKMT peptide substrates with maximum methylation ability are identified.
  • a first substep S1.1 a peptide array with first peptides with amino acid sequences derived from a section of a histone protein is provided. The first peptides have different amino acid sequence variants.
  • a second substep S1.2 at least one first peptide is identified as a substrate, which has a particularly strong methylation ability compared to known substrate peptides of a specific protein lysine methyltransferase. Based on this data, further derived peptides are designed and produced in a third substep 1.3. These derived peptides are 10 to 20 amino acids in length.
  • the loop structure is in particular a structural element in which a folding-back loop (“loop region”) is stabilized by interactions of the amino acids before and after the loop region (“stem region”).
  • Loop region a folding-back loop
  • stem region a folding-back loop
  • Positioning the basic amino acid to be methylated in the center of the loop structure means that the basic amino acid to be methylated is positioned in the loop area.
  • lysine is chosen as the basic amino acid.
  • the methylation ability of these peptides is tested. Steps S1.3 and S1.4 are repeated several times if necessary.
  • the binding of the artificial peptides to the PKMT is optimized.
  • the previously optimized peptides are produced in a first substep S2.1.
  • These peptides have a length in the range of 10 to 20 amino acids and are based on the amino acid sequence of the identified substrate peptide, whereby the amino acid sequence of the derived peptides should enable the formation of a loop structure and a lysine to be methylated should be positioned in the center of the loop structure.
  • At least one peptide is then identified that has a particularly strong binding compared to known substrate peptides of a specific protein lysine methyltransferase.
  • derived peptides are designed and produced in a second substep S2.2.
  • These derived peptides are 10 to 20 amino acids in length. It is essential that the amino acid sequence of the derived, new peptides should enable the formation of a loop structure and that a lysine to be methylated should be positioned in the center of the loop structure.
  • a third substep S2.3 the binding of these peptides to the PKMT is tested.
  • a third design process S3 the inhibition of PKMT is optimized by the artificial peptides.
  • optimized peptides with a length in the range of 10 to 20 amino acids are designed and produced, which are based on the amino acid sequence of the identified substrate peptide, whereby the amino acid sequence of the derived peptides should enable the formation of a loop structure.
  • the inhibition of PKMT by these peptides is then examined in order to identify at least one peptide that exhibits particularly strong inhibition. If necessary, this step can also be repeated in cycles (indicated by dashed lines).
  • FIG. 4 shows a SPOT array on which various peptide sequences derived from the histone 3 protein sequence were synthesized. These were subsequently methylated with the NSD2 PKMT using radiolabeled SAM (Fig. 4a). Different positions show a stronger methylation signal due to the individual amino acid changes. Based on this, peptides were synthesized again on a SPOT array (experiment (2)), which were identified by the initial array. The newly discovered peptides (Tables 1 and 2) show a further increased methylation signal. For example, the peptides in A16, B10, B13 show a stronger methylation signal than H3K36, the natural substrate of NSD2 (A1 and B15) (Fig. 4b).
  • FIG. 5 Shown in Figure 5 are the results of methylation assays used to demonstrate the specificity of peptides obtained in the design process.
  • the autoradiographs on the left show methylation with the PKMT NSD2.
  • the autoradiographs on the left show methylation with the PKMT SETD2.
  • the exposure times are indicated below the autoradiographs. It can be seen that peptide B1 is particularly effectively methylated by NSD2, and peptide B3 by SETD2.
  • the peptide assignment can be found in the table opposite.
  • FIG. 6 shows data from a FRET experiment with peptides in solution, which prove that a peptide according to the invention adopts a loop structure in solution.
  • the example shows data for the histone peptide (H3K36) and a peptide according to the invention (ssK36), which preferentially binds to the PKMT SETD2.
  • the H3K36 and ssK36 peptides were synthesized with an EDANS fluorophore at the C-terminus and a Dabcyl quencher at the N-terminus.
  • EDANS was excited at 340 nm and fluorescence emission was measured at 490 nm. Due to FRET, the fluorescence emission is partially quenched by Dabcyl, and only the remaining fluorescence was measured.
  • the FRET experiments were performed at multiple temperatures starting from 5 °C up to 95 °C using peptide concentrations of 10 pM.
  • H3K36 APATGGVKKPHRYRP ssK36: APRFGGVKRPNRYRP
  • sMD steered molecular simulations
  • the sMD of binding of H3K36 and ssK36 and the SETD2 PKMT were determined with a distance-dependent external force of 0.5 kJ/(mol ⁇ A 2 ) between the Ns atom of K36 and the methyl group C atom of SAM bound in SETD2 is carried out. It was measured how often ssK36 successfully docked to the active site of SETD2 after 50 ns sMD. Criteria used to define a successful docking event are derived from the geometry of the SN2 methyl group transfer transition state known to those skilled in the art.
  • the sMD simulations were performed in the presence and absence of an additional distance-dependent repulsion force of 0.3 kJ/(mol ⁇ A 2 ) between the peptide ends, which prevents the formation of a loop structure.
  • the figure shows the number of successful docking events in 100 sMD simulations with H3K36 or ssK36 based on the SN2 transition state criteria.
  • FIG. 8 shows an autoradiogram of a methylation assay with which the biochemical detection of the inhibitory effect of the peptides obtained in the described design process is carried out.
  • the inhibition of PKMT SETD2 was specifically examined here. Shown is the methylation of a histone protein analog with the characteristic N-terminal tail region of the histone protein H3. The methylation becomes weaker by adding the designed peptide (ssK36), which shows the inhibitory effect of the peptide (left side of the picture).
  • ssK36 designed peptide
  • H3K36 APATGGVKKPHRYRP ssK36: APRFGGVKRPNRYRP

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Abstract

L'invention concerne un peptide artificiel d'une longueur comprise entre 10 et 20 acides aminés dont la séquence d'acides aminés est issue d'une section d'un substrat de la protéine lysine méthyltransférase, le peptide présentant une forte affinité de liaison avec la protéine lysine méthyltransférase, la séquence d'acides aminés permettant de constituer une structure en boucle, et le peptide présentant un effet inhibiteur sur l'activité enzymatique de la protéine lysine méthyltransférase.
PCT/EP2023/067788 2022-06-29 2023-06-29 Peptide artificiel présentant un effet inhibiteur de la pkmt WO2024003227A1 (fr)

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DE102022116235.4 2022-06-29
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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ARAVIND BASAVAPATHRUNI ET AL: "Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L", CHEMICAL BIOLOGY & DRUG DESIGN, BLACKWELL MUNKSGAARD, HOBOKEN, USA, vol. 80, no. 6, 9 October 2012 (2012-10-09), pages 971 - 980, XP072378549, ISSN: 1747-0277, DOI: 10.1111/CBDD.12050 *
ARUNKUMAR DHAYALAN ET AL: "Specificity Analysis-Based Identification of New Methylation Targets of the SET7/9 Protein Lysine Methyltransferase", CHEMISTRY & BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 18, no. 1, 18 November 2010 (2010-11-18), pages 111 - 120, XP028131179, ISSN: 1074-5521, [retrieved on 20101213], DOI: 10.1016/J.CHEMBIOL.2010.11.014 *
CHEN YUAN ET AL: "The role of histone methylation in the development of digestive cancers: a potential direction for cancer management", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 5, no. 1, 3 August 2020 (2020-08-03), XP093081348, Retrieved from the Internet <URL:https://www.nature.com/articles/s41392-020-00252-1> DOI: 10.1038/s41392-020-00252-1 *
KUDITHIPUDI SRIKANTH ET AL: "Substrate Specificity Analysis and Novel Substrates of the Protein Lysine Methyltransferase NSD1", CHEMISTRY & BIOLOGY, vol. 21, no. 2, 1 February 2014 (2014-02-01), GB, pages 226 - 237, XP093081308, ISSN: 1074-5521, DOI: 10.1016/j.chembiol.2013.10.016 *
SCHUHMACHER MAREN KIRSTIN ET AL: "Sequence specificity analysis of the SETD2 protein lysine methyltransferase and discovery of a SETD2 super-substrate", COMMUNICATIONS BIOLOGY, vol. 3, no. 1, 16 September 2020 (2020-09-16), XP093081278, Retrieved from the Internet <URL:https://www.nature.com/articles/s42003-020-01223-6> DOI: 10.1038/s42003-020-01223-6 *

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