Cyclic D-peptides, their derivatives, compositions and uses

Abstract

This disclosure relates to cyclic D-peptides, their derivatives, compositions, and combinations. Specifically, cyclic peptides, their compositions, and derivatives can be made without increasing bilirubin levels. This disclosure also provides the use of cyclic peptides, their derivatives, compositions, and combinations for the treatment and / or prevention of proliferative disorders.

Description

[Technical Field]

[0001] This disclosure relates to novel cyclic D-peptides, as well as their derivatives, compositions, and uses for the treatment of proliferative disorders. [Background technology]

[0002] The following is a list of references considered relevant to the background of the currently disclosed subject matter. -[1] International Publication No. 2006 / 046239 -[2] International Publication No. 2007 / 122622 -[3] International Publication No. 2007 / 091240 -[4] International Publication No. 2008 / 075349 -[5]Sandler, U. et al., 2010, Recent advances in clinical medicine, ISSN:1790-5125. -[6]Sandler, U. et al., 2010, J Experimental Therapeutics and Oncology 8:327-339. -[7] International Publication No. 2015 / 083167 -[8] International Publication No. 2017 / 134668

[0003] The recognition of the above references in this specification should not be inferred to mean that they are in any way related to the patentability of the subject matter currently disclosed.

[0004] Background of the Invention A peptide called "T101," encoded by cDNA specific to the human thymus, has been previously identified. This peptide and its derivatives have been implicated in cancer treatment, particularly through T101's role as an immune system stimulant (International Publication 2006 / 046239, [1]). International Publication 2006 / 046239 demonstrates that T101 can stimulate the immune system and reduce tumor size, suggesting that the peptide influences the proliferation of cancer cells. International Publication 2006 / 046239 also suggests an immune-based role of T101, for example, in protecting patients during the course of standard chemotherapy.

[0005] The treatment of cancer using T101 is also suggested in International Publication No. 2007 / 122622[2], which demonstrates, among other things, the effects of T101 on the development of various types of tumors. Peptide T101 has also been described in International Publication No. 2007 / 091240[3] on the treatment of immune diseases, and in International Publication No. 2008 / 075349[4] on the treatment or prevention of diseases involving cells with T1 / ST2 receptors, and in the publications of Sandler et al.[5-6].

[0006] In addition, a T101 peptide derivative called "Nerofe" has been reported to reduce the secretion of proteins known to be associated with cancer metastasis by cancer cells in vitro, and to directly inhibit cancer cell migration. Furthermore, the peptide has been shown to affect serum levels of vascular endothelial growth factor (VEGF) in cancer patients (International Publication No. 2015 / 083167, [7]), suggesting its use in methods to prevent or treat cancer metastasis.

[0007] Furthermore, the peptide known as "Nerofe" was also shown in International Publication No. 2017 / 134668[8] to be involved in inducing ER stress, which contributes to the promotion of cell death, and was suggested to reduce the standard therapeutic dose of anticancer drugs administered in treated cancer patients. [Overview of the project]

[0008] In a first aspect, the disclosure provides a cyclic peptide or any functional derivative thereof comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys, represented by SEQ ID NO: 1, wherein the amino acid residues of the peptide are D-amino acid residues.

[0009] In a further embodiment, the present disclosure provides a composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and optionally, the composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0010] In another embodiment, the present disclosure provides a pharmaceutical composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0011] In an additional aspect, the present disclosure provides a method for treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder in a subject that needs it, the method comprising administering a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticle or microparticle thereof, or any composition comprising them, wherein the amino acid residues of the peptide are D-amino acid residues.

[0012] In yet another aspect, the present disclosure provides a cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1 (wherein the amino acid residues of the peptide are D-amino acid residues), for use in a method for treating, preventing, ameliorating, reducing or delaying the onset of at least one proliferative disorder, the method comprising administering a therapeutically effective amount thereof, or any functional derivative thereof, or any vehicle, matrix, nanoparticle or microparticle thereof, or any composition comprising them, to a subject that needs it.

[0013] In a further aspect, the present disclosure provides a combination composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1 or any functional derivative thereof (wherein the amino acid residues of the peptide are D-amino acid residues), and at least one anti-cancer agent or any pharmaceutically acceptable salt thereof.

[0014] In a further embodiment, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder, comprising the steps of administering to a subject in need thereof a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof (the amino acid residues of the peptide are D-amino acid residues), at least one anticancer agent, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0015] In another aspect, this disclosure is: (a) A cyclic peptide comprising at least one cyclic peptide or any functional derivative thereof containing the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, and at least one anticancer agent or a pharmaceutically acceptable salt thereof, wherein the amino acid residues of the peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, and optionally included in the first dosage form, (b) A kit comprising at least one anticancer agent, which is optionally included in a second dosage form.

[0016] In a further embodiment, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject exhibiting high bilirubin levels, comprising the step of administering to the subject a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0017] In another aspect, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, the method comprising administering to the subject a therapeutically effective amount of at least one cyclic peptide (where the amino acid residues of the peptide are D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0018] Embodiments are described herein, only as non-limiting examples, with reference to the accompanying drawings, in order to better understand the subject matter disclosed herein and to illustrate how it may actually be carried out. [Brief explanation of the drawing]

[0019] [Figure 1] This shows the cell viability of SHSY5Y, MDA231, and SKBR3 cells after treatment with Nerofe and its derivatives. Cells were treated as follows: untreated (C), treated with Nerofe derivative 1 (1), treated with Nerofe derivative 2 (2), treated with Nerofe derivative 3 (3), treated with Nerofe derivative 4 (4), treated with Nerofe derivative 5 (5), treated with Nerofe derivative 6 (6), treated with Nerofe derivative 7 (7), and treated with the original Nerofe peptide. [Figure 2] This shows the ratio of tumor volume increase in mice injected with CT26 cells. [Modes for carrying out the invention]

[0020] This disclosure relates to the first D-cyclic peptides and several derivatives thereof that exhibit strong therapeutic effects, particularly against cancer cells.

[0021] In a first aspect, the disclosure provides a cyclic peptide or any functional derivative thereof comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys, represented by SEQ ID NO: 1, wherein the amino acid residues of the peptide are D-amino acid residues.

[0022] As used herein, the term “cyclic peptide” encompasses a peptide molecule comprising the amino acid sequence shown by SEQ ID NO: 1 (i.e., the amino acid sequence Trp Trp Thr Phe Phe Leu Pro Ser Thr Leu Trp Glu Arg Lys, all in D conformation), or any derivative thereof comprising the amino acids shown by any one of SEQ ID NOs: 1-10, referred herein as “dTCApF” or “Nerofe,” where the amino acid sequence forms a cyclic structure. The cyclic peptides of this disclosure also relate to functional derivatives of the amino acid sequence shown by SEQ ID NO: 1 (e.g., comprising the amino acids shown by any one of SEQ ID NOs: 2-10) or pharmaceutically acceptable salts of cyclic peptides. Any pharmaceutically acceptable salt of a cyclic peptide as defined herein is encompassed in this disclosure.

[0023] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 1. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 1.

[0024] In some embodiments, the cyclic peptide of the present disclosure further comprises n polyethylene glycol (PEG) moieties, the peptide having the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) (wherein n is the number of PEG moieties and is an integer from 1 to 10).

[0025] In some embodiments, n is 1, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 2.

[0026] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 2.

[0027] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 3.

[0028] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 3. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 3.

[0029] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 4.

[0030] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 4. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 4.

[0031] In some further embodiments, n is an integer from 1 to 100, specifically, in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 2 0, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47 n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99, or n is 100.

[0032] In some embodiments, the cyclic peptide of the present disclosure further comprises n sarcosine (Sar) residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)) (wherein n is the number of Sar residues and is an integer from 1 to 10). In some embodiments, n is 1, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 5.

[0033] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 5. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 5.

[0034] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 6.

[0035] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 6. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 6.

[0036] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 7.

[0037] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 7. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 7.

[0038] In some further embodiments, n is an integer from 1 to 100, specifically, in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 2 0, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47 n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99, or n is 100.

[0039] In some embodiments, the cyclic peptide of this disclosure comprises amino acids represented by SEQ ID NO: 8.

[0040] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 8. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 8.

[0041] In some embodiments, the cyclic peptide of the present disclosure further comprises n glycine (Gly) residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)) (wherein n is the number of Gly residues and is an integer from 1 to 10). In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 9.

[0042] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 9. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 9.

[0043] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 10.

[0044] In some embodiments, the cyclic peptide or its functional derivative comprises amino acids having at least 70%, 80%, 90%, or 95% identity with the corresponding sequence of SEQ ID NO: 10. In some specific embodiments, the cyclic peptide of the present disclosure consists of the amino acid sequence of SEQ ID NO: 10.

[0045] In some further embodiments, n is an integer from 1 to 100, specifically, in some embodiments, n is 1, n is 2, n is 3, n is 4, n is 5, n is 6, n is 7, n is 8, n is 9, n is 10, n is 11, n is 12, n is 13, n is 14, n is 15, n is 16, n is 17, n is 18, n is 19, n is 2 0, n is 21, n is 22, n is 23, n is 24, n is 25, n is 26, n is 27, n is 28, n is 29, n is 30, n is 31, n is 32, n is 33, n is 34, n is 35, n is 36, n is 37, n is 38, n is 39, n is 40, n is 41, n is 42, n is 43, n is 44, n is 45, n is 46, n is 47 n is 48, n is 49, n is 50, n is 51, n is 52, n is 53, n is 54, n is 55, n is 56, n is 57, n is 58, n is 59, n is 60, n is 61, n is 62, n is 63, n is 64, n is 65, n is 66, n is 67, n is 68, n is 69, n is 70, n is 71, n is 72, n is 73, n is 74, n is 75, n is 76, n is 77, n is 78, n is 79, n is 80, n is 81, n is 82, n is 83, n is 84, n is 85, n is 86, n is 87, n is 88, n is 89, n is 90, n is 91, n is 92, n is 93, n is 94, n is 95, n is 96, n is 97, n is 98, n is 99, or n is 100.

[0046] Surprisingly, in Example 6, the cyclic peptide of the present disclosure was demonstrated to be a safe compound because it did not increase bilirubin levels upon injection into mice.

[0047] In some embodiments, the cyclic peptides of the Disclosure may not increase bilirubin levels upon administration (e.g., to a target requiring attention). In some specific embodiments, the cyclic peptides of the Disclosure may maintain bilirubin levels (e.g., to a target requiring attention). In some specific embodiments, the cyclic peptides of the Disclosure may not alter or change bilirubin levels upon administration (e.g., to a target requiring attention).

[0048] The term "peptide" as defined herein refers to a molecular chain of amino acid residues, which may be modified at one of the amino acid residues as needed, for example, by manosylation, glycosylation, amidation (e.g., C-terminal amide), carboxylation, or phosphorylation. Peptides can be obtained synthetically by genetic engineering, expression in host cells, or any other suitable means. Methods for producing peptides and cyclic peptides as described above are well known in the art.

[0049] More specifically, an "amino acid molecule," "amino acid sequence," or "peptide sequence" is the order in which amino acid residues linked by peptide bonds exist within a peptide or protein chain. Sequences are generally reported from the N-terminus containing a free amino group to the C-terminus containing an amide. While an amino acid sequence is often called a peptide or protein sequence when it represents the primary structure of a protein, a protein is defined as an amino acid sequence that has folded into a specific three-dimensional configuration and undergone post-translational modifications such as phosphorylation, acetylation, glycosylation, manosylation, amidation, carboxylation, sulfhydryl bond formation, and cleavage. Therefore, the terms "amino acid sequence" or "peptide sequence" should be distinguished from the term "protein."

[0050] As used herein, amino acids refer to natural and synthetic amino acids, as well as amino acid analogs and amino acid mimes that function similarly to natural amino acids. Natural amino acids are those encoded by the genetic code, as well as those that are later modified (e.g., hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine). "Amino acid analogs" refer to compounds that have the same basic chemical structure as natural amino acids, i.e., hydrogen, a carboxyl group, an amino group, and an α-carbon bonded to an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have a modified R group or a modified peptide skeleton but retain the same basic chemical structure as natural amino acids. "Amino acid mimes" refer to compounds that have a structure different from the general chemical structure of amino acids but function similarly to natural amino acids. Amino acids may be referred herein by either their commonly known three-letter or one-letter symbols as recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0051] As used herein, the term “amino acid” refers to natural and synthetic amino acid residues, as well as amino acid analogs and amino acid mimes that function similarly to natural amino acids. Natural amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine.

[0052] The term amino acid encompasses both L-amino acids and D-amino acids, which are mirror images of L-amino acids with reversed chirality at carbon alpha. D-amino acids are highly resistant to protease-mediated degradation and have a low immunogenicity response.

[0053] The terms "amino acid sequence" or "peptide sequence" also refer to the order in which amino acid residues linked by peptide bonds are located within a peptide or protein chain. Sequences are generally reported from the N-terminus, which contains a free amino group, to the C-terminus, which contains a free carboxyl group.

[0054] As described above, this disclosure also includes cyclic peptides, including derivatives of peptides having the amino acid sequence shown by SEQ ID NO: 1 (for example, including the amino acids shown by any one of SEQ ID NOs: 2-10). The term “derivatives” means peptides that include any one of the amino acids shown by the amino acid sequence shown by SEQ ID NO: 1 or any one of SEQ ID NOs: 2-10, but in which one or more amino acids differ in the entire sequence, i.e., peptides having deletions, substitutions (e.g., substitution of at least one amino acid with another), inversions, or additions in the entire sequence of SEQ ID NO: 1 and any one of SEQ ID NOs: 2-10. This term also includes substitutions of at least one amino acid residue in the entire sequence by its respective L amino acid residue.

[0055] In certain embodiments, the modified cyclic peptide of the present disclosure or the composition of the invention has at least 70%, 80%, 90%, 95%, or particularly 99% identity with the sequence corresponding to SEQ ID NO: 1 and any one of SEQ ID NOs: 2-10.

[0056] In some embodiments, a cyclic peptide comprising the amino acid sequence represented by SEQ ID NO: 1 or any one of SEQ ID NOs: 2-10 may contain one or more amino acid residues substituted by conservative substitutions, without significantly affecting the biological characteristics of the modified peptide, compared to an unmodified peptide having the amino acid sequence of SEQ ID NO: 1 or any one of SEQ ID NOs: 2-10.

[0057] Amino acid "substitution" is the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, i.e., a conserved amino acid substitution. Amino acid substitutions can be made based on the similarity of the properties of the residues involved in terms of polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or amphiphilicity. For example, each of the following eight groups contains amino acids that are conserved substitutions of each other. 1) Alanine (A), Glycine (G), 2) Aspartic acid (D), glutamic acid (E), 3) Asparagine (N), glutamine (Q), 4) Arginine (R), Lysine (K), 5) Isoleucine (I), leucine (L), methionine (M), valine (V), 6) Phenylalanine (F), tyrosine (Y), tryptophan (W), 7) Serine (S), threonine (T), and 8) Cysteine ​​(C), Methionine (M).

[0058] It is understood that these peptide derivatives should not alter the biological activity of the original peptide. The term "functional" means that the modified peptide (i.e., derivative) retains biological activity qualitatively similar to that of the unmodified peptide. The biological activity of the derivative can be determined by monitoring the effect of the derivative upon administration to an animal model, as described herein, i.e., as known in the art.

[0059] In certain embodiments, the Disclosure relates to functional derivatives or functional fragments of a cyclic polypeptide comprising an amino acid sequence represented by SEQ ID NO: 1 or any one of SEQ ID NOs: 2-10, wherein the functional derivative or functional fragment has an amino acid sequence that is at least about 70%, 75%, 80%, 85%, 90%, or 95%, particularly 99%, identical to the amino acid sequence of the unmodified isolated polypeptide of the present invention, i.e., the amino acid sequence represented by SEQ ID NO: 1 or any one of SEQ ID NOs: 2-10, and retains biological activity qualitatively similar to that of the unmodified peptide.

[0060] In some specific embodiments, the cyclic peptide consists of one amino acid sequence from SEQ ID NO: 1 or SEQ ID NOs: 2-10.

[0061] Therapeutic peptides can be modified using several types of derivatives to improve their stability, bioavailability, and pharmacokinetic properties, such as PEGylation, addition of N-methyl amino acids (e.g., sarcosine), addition of glycine residues, and addition of fatty acid chains (acylation), acylation, glycosylation, phosphorylation, and introduction of sulfur-containing groups into the peptide backbone (thioether derivatives).

[0062] In some embodiments, the cyclic peptide derivatives of the present invention include at least a PEG moiety. PEG (polyethylene glycol) is a synthetic polymer that can be attached to therapeutic peptides as a “PEG moiety” or “PEGylated” to modify their physicochemical and pharmacokinetic properties. PEGylated involves covalently attaching PEG to a peptide molecule, typically at the N-terminus or C-terminus, or to a specific amino acid residue. This modification can provide the peptide with several advantages that may affect pharmacokinetics, biodistribution, and therapeutic outcomes, such as increased half-life, improved solubility and stability, enhanced bioavailability, and reduced toxicity. By reducing immunogenicity and nonspecific binding to tissues, PEGylated can not only contribute to reducing the toxicity profile of peptides but also provide the peptide with modifiable properties (e.g., their size, charge, and hydrophobicity).

[0063] In some embodiments, the cyclic peptide derivatives of the present invention involve the addition of at least one glycine residue. Adding a glycine residue to a therapeutic peptide makes it possible to improve its pharmacokinetic properties. Glycine is the smallest amino acid and is highly flexible, meaning that glycine can introduce flexibility and conformational variability into the peptide structure. This can be beneficial for several reasons, as it can improve solubility, reduce immunogenicity, increase half-life, and enhance receptor selectivity.

[0064] In some embodiments, the cyclic peptide derivatives of the present invention include the addition of at least one sarcosine residue or N-methylglycine. Sarcosine is a non-proteinogenic amino acid that can be added to therapeutic peptides to modify their properties. The addition of sarcosine can improve the pharmacokinetic profile of peptides by providing several advantages, including increased stability, improved solubility, reduced immunogenicity, enhanced receptor selectivity, and reduced toxicity.

[0065] In some further embodiments, the cyclic peptide of the present disclosure may further comprise one or more targeting moieties selected from the group consisting of antibodies, antibody fragments, aptamers, and small molecules. In some embodiments, the targeting moieties may be directly or indirectly bound to or conjugated to the cyclic peptide.

[0066] In some further embodiments, the peptide is directly or indirectly bound or conjugated to at least one therapeutic compound.

[0067] In some embodiments, at least one therapeutic compound according to the present disclosure may be an anticancer agent. In some embodiments, the anticancer agent according to the present invention may be a chemotherapeutic agent, an immunotherapy agent (e.g., an antibody, antibody fragment or monoclonal antibody that downregulates inhibitory immune receptors), an immunostimulant, a Bcl2 inhibitor, a tyrosine kinase inhibitor, a hormone, a bioagent, a differentiation-inducing factor, an anti-angiogenic factor, or an anti-autophagy agent.

[0068] In some specific embodiments, at least one therapeutic agent may be doxorubicin. In some embodiments, at least one therapeutic agent may be a BCL2 inhibitor. In some further alternative embodiments, at least one therapeutic agent may be an anti-cancer immunotherapy agent, such as an anti-PD1 antibody or an anti-PDL1 antibody.

[0069] In a further embodiment, the present disclosure provides a composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and optionally, the composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0070] In some embodiments, at least one cyclic peptide of the composition of the Disclosure is as defined in the earlier aspects of the Disclosure described in detail above.

[0071] In some embodiments, the compositions of the present disclosure are intended for use in methods for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

[0072] In some embodiments, the composition is a pharmaceutical composition.

[0073] In some embodiments, the cyclic peptides of the compositions of the present disclosure can not increase bilirubin levels upon administration (e.g., to a target requiring it). In some specific embodiments, the cyclic peptides of the compositions of the present disclosure can maintain bilirubin levels upon administration (e.g., to a target requiring it). In some embodiments, the cyclic peptides of the compositions of the present disclosure can not (change or alter) bilirubin levels upon administration (e.g., to a target requiring it).

[0074] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0075] In some embodiments, at least one cyclic peptide of the pharmaceutical composition of the present disclosure is as defined in the earlier aspects of the present disclosure described in detail above.

[0076] In some embodiments, the pharmaceutical compositions of this disclosure are intended for use in methods for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

[0077] In some embodiments, the proliferative disorders associated with the compositions of the present invention may be at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS-mutated cancer, mCRC mtKRAS cancer, and / or melanoma. Further proliferative disorders associated with the compositions of the present invention are defined in subsequent embodiments of the present disclosure as defined below.

[0078] In some embodiments, the cyclic peptides of the pharmaceutical compositions of the Disclosure may not increase bilirubin levels upon administration (e.g., to a target requiring treatment). In some specific embodiments, the cyclic peptides of the pharmaceutical compositions of the Disclosure may maintain bilirubin levels upon administration (e.g., to a target requiring treatment). In some embodiments, the cyclic peptides of the pharmaceutical compositions of the Disclosure may not alter or change bilirubin levels upon administration (e.g., to a target requiring treatment).

[0079] The term “pharmaceutical composition” as defined herein means the cyclic peptide of the present invention or any derivative thereof, optionally at least one pharmaceutically acceptable excipient or carrier known in the art. As used herein, “pharmaceutically acceptable carrier” includes all kinds of solvents, dispersion media, coatings, antimicrobial agents, and antifungal agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition is intended. Pharmaceutical compositions used to treat subjects in need thereof according to this disclosure may also optionally include buffers, agents that adjust their osmotic pressure, and optionally one or more pharmaceutically acceptable additives known in the art. Pharmaceutical compositions according to the present invention, used to treat subjects in need of treatment, which can be conveniently provided in unit dosage forms, may be prepared according to prior art well known in the pharmaceutical industry, for example, as detailed in the following examples. In addition to the components specifically mentioned herein, it should be understood that compositions according to this disclosure may also include other agents standard in the art, taking into account the type of formulation in question.

[0080] In an additional aspect, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject requiring such treatment, comprising the steps of administering a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, or any composition comprising them, wherein the amino acid residues of the peptide are D-amino acid residues.

[0081] In some embodiments, the cyclic peptide of the method of the present disclosure further comprises n PEG moieties, the peptide having the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) (wherein n is the number of PEG moieties and is an integer from 1 to 10).

[0082] In some embodiments, the cyclic peptide of the method of the present disclosure comprises the amino acid sequence shown by SEQ ID NO: 2.

[0083] In some embodiments, the cyclic peptide of the method of the present disclosure comprises the amino acid sequence shown by SEQ ID NO: 3.

[0084] In some embodiments, the cyclic peptide of the method of the present disclosure comprises the amino acid sequence shown by SEQ ID NO: 4.

[0085] In some embodiments, the cyclic peptide of the method of the present disclosure further comprises n sarcosine residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)) (wherein n is the number of Sar residues, and is an integer from 1 to 10).

[0086] In some embodiments, n is 1, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 5.

[0087] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 6.

[0088] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 7.

[0089] In some embodiments, the cyclic peptide of the method of the present disclosure comprises amino acids represented by SEQ ID NO: 8.

[0090] In some embodiments, the cyclic peptide of the method of the present disclosure further comprises n glycine (Gly) residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)) (wherein n is the number of Gly residues and is an integer from 1 to 10).

[0091] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 9.

[0092] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 10.

[0093] In some embodiments, the peptide of the method of the present disclosure is directly or indirectly bound or conjugated to at least one therapeutic compound.

[0094] In some embodiments, at least one cyclic peptide of the method of the present disclosure is as defined in the earlier aspects of the present disclosure described in detail above.

[0095] As used herein, “proliferative disorder” refers to a disorder characterized by excessive proliferation. This term means cell division and growth that are not part of the normal cellular turnover, metabolism, growth, or proliferation of the whole organism. Unwanted cell proliferation is seen in tumors and other pathological proliferations of cells, which do not perform normal function and, for the most part, continue uninhibited at a rate exceeding the proliferation rate of cells in normal tissue in the absence of external intervention. Pathological conditions resulting from unwanted cell proliferation are referred herein as “hyperproliferative disorders” or “hyperproliferative disorders.” It should be noted that the terms “proliferative disorder,” “cancer,” “tumor,” and “malignant tumor” are all equivalent to the hyperplasia of tissue or organ. In general, the compositions and methods of the present invention may be used for the treatment of non-solid tumors and solid tumors.

[0096] In some embodiments, proliferative disorder may refer to a malignant tumor. The malignant tumor intended in the present invention may be any one of lymphoma, leukemia, carcinoma, melanoma, myeloma, and sarcoma.

[0097] In some embodiments, proliferative disorders can refer to lymphoma. Lymphoma is a cancer of the lymphoid cells of the immune system. Typically, lymphoma exists as a solid tumor of lymphoid cells. These malignant cells often originate from lymph nodes and manifest as enlargement (tumor) of the lymph nodes. It can also affect other organs, in which case it is called extranodular lymphoma. Non-specific examples of lymphoma include Hodgkin's disease, non-Hodgkin lymphoma, and Burkitt's lymphoma.

[0098] In some embodiments, proliferative disorders may refer to leukemia. Leukemia refers to a progressive malignant disease of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease—acute or chronic, (2) the type of cells involved—myeloid, lymphoid, or monocytic, and (3) an increase or non-increase in the number of abnormal cells in the blood—leukemia or non-leukemia (subleukemia).

[0099] In some embodiments, proliferative disorder may refer to carcinoma. As used herein, carcinoma refers to an invasive malignant tumor consisting of transformed epithelial cells. Alternatively, this refers to a malignant tumor consisting of transformed cells of unknown histogenesis but possessing specific molecular or histological features associated with epithelial cells (e.g., the formation of cytokeratin or intercellular crosslinks).

[0100] In some embodiments, proliferative disorder may refer to melanoma. Melanoma, as used herein, is a malignant tumor of melanocytes. Melanocytes are cells that produce melanin, the dark pigment that gives skin its color. They are primarily found in the skin, but can also be found in other parts of the body, including the intestines and eyes. Melanoma can occur in any part of the body that contains melanocytes.

[0101] In some embodiments, proliferative disorders may refer to sarcomas. Sarcomas are cancers that arise from transformed connective tissue cells. These cells originate from the embryonic mesoderm or intermediate layer that forms bone, cartilage, and adipose tissue. This is in contrast to carcinomas that originate from epithelium. Epithelium covers the surface of structures throughout the body and is the origin of cancers in the breast, colon, and pancreas.

[0102] In some embodiments, proliferative disorders may refer to myeloma. Myeloma as referred to herein is a cancer of plasma cells, a type of white blood cell normally involved in antibody production. Clusters of abnormal cells accumulate in the bone, where they cause bone lesions, and in the bone marrow, where they interfere with the production of normal blood cells. Most cases of myeloma also cause kidney problems and are characterized by the production of paraproteins, which are abnormal antibodies that can interfere with normal antibody production and lead to immunodeficiency. Hypercalcemia (high calcium levels) is frequently encountered.

[0103] In some embodiments, proliferative disorders may refer to hematological malignancies (including lymphoma, leukemia, and myeloproliferative disorders), dysplastic and aplastic anemia (both virally induced and idiopathic), myelodysplastic syndromes, all types of paraneoplastic syndromes (both immune-mediated and idiopathic), and solid tumors (at least one of the following: GI duct, colorectal, lung, liver, breast, prostate, pancreatic, and Kaposi's sarcoma). In some embodiments, the malignancy may be lymphoma.

[0104] In some embodiments, proliferative disorders may refer to at least one of hematopoietic malignancies, e.g., all types of lymphoma, leukemia, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mutated KRAS tumor, chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), mast cell leukemia, hairy cell leukemia, Hodgkin's disease, non-Hodgkin lymphoma, Burkitt lymphoma, and / or multiple myeloma.

[0105] In some embodiments, the methods of the present disclosure may relate to the treatment or inhibition of at least one of the following solid tumors: for example, tumors of the lips and oral cavity, pharynx, paranasal sinuses, major salivary glands, thyroid gland, esophagus, stomach, small intestine, colon, colorectal cavity, anal canal, liver, gallbladder, extrahepatic bile ducts, ampulla of Vater, exocrine pancreas, lung, pleural mesothelioma, bone, soft tissue sarcoma, skin, breast, vulva, vagina, cervix, uterine body, ovary, fallopian tube, choriocarcinoma of pregnancy, penis, prostate, testicle, kidney, renal pelvis, ureter, bladder, urethra, eyelid carcinoma, conjunctival carcinoma, malignant melanoma of the conjunctiva, malignant melanoma of the uvea, retinoblastoma, lacrimal gland carcinoma, orbit, brain, spinal cord, vascular system sarcoma, angiosarcoma, and / or Kaposi's sarcoma.

[0106] In some specific embodiments, proliferative disorders may refer to mutant KRAS tumors. In some specific embodiments, the cyclic peptides, compositions, or methods of the present invention are for treating, preventing, improving, reducing, or delaying the onset of mutant KRAS tumors. Mutant KRAS tumors, or KRAS-driven tumors, are associated with a type of cancerous tumor in which the Kirsten rat sarcoma virus oncogene (KRAS) is mutated. The KRAS oncogene has the highest mutation rate of all cancers and is associated with a lineage of highly lethal cancers, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC).

[0107] In some embodiments, the proliferative disorder is at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS mutation cancer, mCRC mtKRAS cancer, and / or melanoma.

[0108] The above definitions and embodiments relating to proliferative disorders are applicable to any further preferred embodiments of this disclosure.

[0109] In some embodiments, the method of the present disclosure includes administering a composition comprising at least one cyclic peptide as defined in the earlier aspects of the present disclosure described in detail above.

[0110] In some embodiments, the composition is a pharmaceutical composition, and optionally further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0111] In some embodiments, the method of the present disclosure further includes administering at least one additional anticancer agent.

[0112] In some specific embodiments, the at least one additional anticancer agent may be at least one of doxorubicin, taxol, cisplastin, BCL2 inhibitors, and / or anticancer immunotherapy agents (e.g., anti-PD1 antibody or anti-PDL1 antibody).

[0113] The term "anti-cancer drug," also known as "anti-neoplastic drug," is used in a broader sense to encompass any drug or agent effective in treating malignant or cancerous diseases. Several classes of anti-cancer drugs exist, as will be further detailed below.

[0114] In some embodiments, the anticancer agents according to this disclosure are chemotherapeutic agents, immunotherapeutic agents (e.g., antibodies, antibody fragments, or monoclonal antibodies that downregulate inhibitory immune receptors), immunostimulants, Bcl2 inhibitors, tyrosine kinase inhibitors, hormonal agents, bioagents, differentiation-inducing factors, anti-angiogenic factors, or anti-autophagy agents.

[0115] In some embodiments, the anticancer agents according to this disclosure are chemotherapeutic agents. “Chemotherapeutic agents” known in the art are drugs that target cells at different stages of the process of new cell formation and are used to treat cancer by killing cancer cells or inhibiting their growth. These drugs can be administered orally, intravenously, or by injection. Non-limiting examples of chemotherapeutic agents include anthracyclines (e.g., doxorubicin), which act by inhibiting an enzyme called topoisomerase II, which is involved in DNA replication and repair, leading to the death of cancer cells; mitotic inhibitors (these drugs kill cancer cells by interfering with the mitotic spindle fibers of cells, which are necessary for cell division, e.g., paclitaxel (Taxol), vinblastine, and docetaxel); alkylating agents (these drugs act by damaging the DNA of cancer cells, preventing them from dividing and proliferating, e.g., cyclophosphamide, cisplatin, and carmustine); and antimetabolites (these drugs interfere with the proliferation and mitotic capacity of cancer cells, which are necessary for DNA / RNA synthesis). Drugs that are similar in quality and structure (e.g., methotrexate, 5-fluorouracil, and gemcitabine), topoisomerase inhibitors (these drugs prevent the unwinding of DNA during replication, causing DNA damage and inhibiting cell proliferation (e.g., etoposide, irinotecan, and topotecan)), hormonal agents (these drugs target hormone-driven cancer cells such as breast and prostate cancer, acting by blocking the hormones or receptors that cancer cells use to proliferate (e.g., tamoxifen, letrozole, and bicalutamide)), and immunomodulators (these drugs act by enhancing the immune system's ability to detect and destroy cancer cells (e.g., interferon-α and interleukin-2)).

[0116] In some embodiments, the anticancer agent according to this disclosure is doxorubicin. Doxorubicin (also known as Adriamycin or Doxil), having the systematic (IUPAC) name (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione, is an antitumor antibiotic obtained from Streptomyces peucetius. Doxorubicin is an anthracycline poisomerase inhibitor that intercalates between base pairs in DNA helices, thereby preventing DNA replication and ultimately inhibiting protein synthesis. Furthermore, doxorubicin inhibits topoisomerase II, resulting in an increase and stabilization of enzyme-DNA binding complexes that can be cleaved during DNA replication, and subsequently preventing nucleotide chain ligation after double-strand breaks. Doxorubicin also forms oxygen free radicals (ROS), leading to cytotoxicity secondary to lipid peroxidation of cell membrane lipids. Any derivative of doxorubicin is incorporated herein.

[0117] In some embodiments, the anticancer agent according to this disclosure is cisplatin. Cisplatin, cisplatin, or cis-diamminedichloroplatin(II) (Cl2H6N2Pt), having the systematic (IUPAC) name (SP-4-2)-diamminedichloroplatin(II), is a platinum-based chemotherapeutic agent used to treat various types of cancer, and was the first member of its class, which now also includes carboplatin and oxaliplatin. Cisplatin functions by forming intra- and inter-strand crosslinks within DNA, resulting in inhibition of DNA replication and transcription. These crosslinks disrupt cellular processes and ultimately induce apoptosis in cancer cells. Furthermore, cisplatin exhibits its cytotoxic effects by activating cellular pathways involved in apoptosis and inhibiting DNA repair mechanisms. Any analogues, derivatives, or formulations of cisplatin that fall within the scope of the claims are encompassed by this patent disclosure.

[0118] In some embodiments, the anticancer agent according to this disclosure is Taxol.

[0119] Taxol (also known as paclitaxel), whose systemic (IUPAC) name is (2α,4α,5β,7β,10β,13α)-4,10-bis(acetyloxy)-13-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20-epoxytax-l-en-2-ylbenzoate, is a chemotherapeutic agent derived from the bark of the Pacific yew (Taxus brevifolia). Taxol is classified as a member of the taxane family. It functions as a microtubule stabilizer by binding to the β-subunit of tubulin within microtubules, promoting polymerization and inhibiting depolymerization. This mechanism disrupts the dynamic equilibrium of microtubule assembly and degradation, leading to mitotic arrest during cell division. Furthermore, taxol induces apoptosis by activating intracellular signaling pathways. The antitumor activity of taxol primarily targets rapidly dividing cells and is effective against various solid tumors, including ovarian cancer, breast cancer, and lung cancer. Any derivative or analogue of taxol falls within the scope of this description.

[0120] In some embodiments, the anticancer agents according to this disclosure are immunotherapeutic agents. In the context of this disclosure, the terms “immunotherapeutic agent” or “immunostimulator” refer to cancer immunotherapy that seeks to destroy tumors by stimulating the immune system. Immunotherapy is a type of cancer treatment that utilizes the body’s immune system to fight cancer cells. Several types of immunotherapeutic agents exist, including monoclonal antibodies, checkpoint inhibitors, CAR T-cell therapy, and oncolytic viruses.

[0121] In some embodiments, the anticancer agents according to this disclosure are monoclonal antibodies. Monoclonal antibodies help the immune system recognize and attack cancer cells more effectively, for example, nivolumab, pembrolizumab, or spartalizumab are effective against programmed cell death protein 1 (PD-1), atezolizumab, durvalumab, or avelumab are effective against programmed cell death receptor ligand 1 (PD-L1), trastuzumab (Herceptin) is effective against HER2-positive breast cancer, and rituximab (Rituxan) is effective against certain lymphomas.

[0122] In some embodiments, the anticancer agents according to this disclosure are checkpoint inhibitors. Checkpoint inhibitors are drugs that block proteins on immune cells called checkpoints, which cancer cells can use to evade the immune system. By blocking these checkpoints, checkpoint inhibitors can help the immune system recognize and attack cancer cells. Non-exclusive examples of checkpoint inhibitors used in cancer immunotherapy include pembrolizumab (Keytruda) and nivolumab (Opdivo).

[0123] In some embodiments, the anticancer agents of this disclosure refer to CAR T-cell therapy. CAR T-cell therapy is a type of immunotherapy that involves genetically modifying a patient's T cells (a type of immune cell) to better recognize and attack cancer cells. CAR T-cell therapy has shown promise in the treatment of certain types of hematological cancers, such as leukemia and lymphoma.

[0124] In some embodiments, the anticancer agents according to this disclosure are oncolytic viruses. Oncolytic viruses are viruses that have been modified to infect and kill cancer cells while leaving healthy cells intact. Oncolytic viruses may also help stimulate the immune system to attack cancer cells. A non-limiting example of an oncolytic virus used in cancer immunotherapy is tarimodine laherparebeck (T-VEC) for melanoma.

[0125] In some embodiments, the anticancer agents according to this disclosure are anti-PDL1 agents. Anti-PDL1 agents, also known as programmed cell death ligand 1 inhibitors as used herein, are therapeutic compounds used to treat a variety of cancers. They function by interfering with the interaction between programmed cell death ligand 1 (PDL1) and its receptor, programmed cell death protein 1 (PD1), thereby preventing the suppression of the immune response against cancer cells. This inhibition ultimately amplifies the activity of cytotoxic T lymphocytes and other immune cells, leading to the eradication of tumor cells. Anti-PDL1 agents include monoclonal antibodies, small molecules, fusion proteins, and other pharmacologically active compounds specifically designed to target the PDL1 / PD1 pathway. Any compounds, compositions, or formulations capable of modulating the PDL1 / PD1 interaction for therapeutic purposes are included within the scope of this disclosure.

[0126] In some specific embodiments, the anti-PDL1 agent may be a monoclonal antibody. In some further specific embodiments, the anti-PDL1 antibody may be one of atezolizumab (trade name: Tecentriq), durvalumab (trade name: Imfinzi), and avelumab (trade name: Bavencio).

[0127] In some embodiments, the anticancer agents according to this disclosure are anti-PD1 agents. Anti-PD1 agents, also known as programmed cell death protein 1 inhibitors as used herein, are therapeutic compounds used to treat a variety of cancers. These agents bind to the PD1 receptor on T cells, thereby blocking the interaction between PD1 and its ligands, including PDL1 and programmed cell death ligand 2 (PDL2), which are expressed on tumor cells and antigen-presenting cells. By releasing the inhibition against T cells, anti-PD1 agents exert the immune system's ability to recognize and attack cancer cells, providing broad efficacy across various cancer types, regardless of PDL1 expression levels. Anti-PD1 agents include monoclonal antibodies, small molecules, fusion proteins, and other pharmacologically active compounds specifically designed to target the PD1 pathway. Any compound, composition, or formulation capable of modulating the PD1 pathway for therapeutic purposes is included within the scope of this disclosure.

[0128] In some specific embodiments, the anti-PD1 agent may be a monoclonal antibody. In some further specific embodiments, the anti-PD1 antibody may be one of pembrolizumab (trade name: Keytruda), nivolumab (trade name: Opdivo), and cemiprimab (trade name: Libtayo).

[0129] In some embodiments, the anticancer agents according to this disclosure are Bcl2 inhibitors. “Bcl-2 inhibitors” is a class of drugs that target the B-cell lymphoma 2 (Bcl-2) protein family. Bcl-2 is a group of proteins that play a crucial role in regulating apoptosis, or programmed cell death. Overexpression of Bcl-2 proteins can lead to cancer cell survival and make cancer cells resistant to chemotherapy and radiotherapy. Therefore, Bcl-2 inhibitors are designed to bind to Bcl-2 proteins, preventing them from inhibiting apoptosis and resulting in inhibition of cell death and tumor growth. Bcl-2 inhibitors are being studied for their potential therapeutic use in various cancers, including lymphoma, leukemia, and solid tumors.

[0130] In some embodiments, Bcl2 inhibitors may bind to and antagonize any one of the human Bcl-2 viability-promoting proteins, Mcl-1, Bcl-w, Bcl2A1, and Bcl-B / Bcl2L10, represented by accession numbers NP_068779.1, AAB09055, NP_004040.1, and NP_001293097.1, respectively.

[0131] In some other embodiments, at least one inhibitor of the Bcl2 viability protein is at least one Bcl-2 homology 3 (BH3) mimetic compound. BH3 mimetic drugs are a class of anticancer drugs that mimic the action of BH3-only proteins by binding to viability proteins such as BCL2 in the same manner and inhibiting BCL2's ability to bind to BAX or BAK.

[0132] In some specific embodiments, the anticancer agent according to this disclosure may be a BH3 mimetic compound. In some specific embodiments, the BH3 mimetic compound is 4-{4-[(4'-chloro[1,1'-biphenyl]-2-yl)methyl]piperazine-1-yl}-N-(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)benzamide (ABT-737), 4-(4-{[2-(4-chlorophenyl)-4,4 -dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]-pyridine-5-yloxy)benzamide (venetoclax or ABT-199), 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1- [en-1-yl]methyl}piperazine-1-yl)-N-(4-{[(2R)-4-(morpholine-4-yl)-1-(phenylsulfanyl)butane-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)-benzamide (Navitocrax or ABT-263), 2-(2-((3,5-dimethyl-1H-pyrrole-2-yl)methylene)-3-methoxy-2H- It is at least one of the following: pyrrole-5-yl)-1H-indole (Obatoclax or GX15-070), or 3-[1-(1-adamantylmethyl)-5-methylpyrazole-4-yl]-6-[8-(1,3-benzothiazole-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyridine-2-carboxylic acid (A-1331852), or a combination thereof.

[0133] In some further embodiments, the inhibitor of Bcl2 viability-promoting protein or BH3 mimetic compound is 4-{4-[(4'-chloro[1,T'-biphenyl]-2-yl)methyl]piperazine-l-yl}-N-(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonylbenzamide (ABT-737), or any pharmaceutically acceptable salt or hydrate thereof, or any stereoisomer or salt thereof.

[0134] In some specific embodiments, the anticancer agent according to this disclosure is ABT-737. ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the evolutionarily conserved Bcl-2 family of proteins that share a Bcl-2 homology (BH) domain. ABT-737 is not bioavailable after oral administration, leading to the development of Navitocrax (ABT-263) as an orally available derivative with similar activity against small cell lung cancer (SCLC) cell lines. The systematic (IUPAC) name of ABT-737 is 4-{4-[(4'-chloro[1,T-biphenyl]-2-yl)methyl]piperazine-1-yl}-N-(4-{[(2R)-4-(dimethylamino)1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)benzamide(C 42 H 45 It is CIN6O5S2 (CAS number: 852808-04-9). The molecular weight of ABT-737 is 813.43 g / mol.

[0135] In some further embodiments, the inhibitor of Bcl2 viability-promoting protein or BH3 mimetic compound is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-l-cyclohexen-l-yl]methyl}l-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]-pyridine-5-yloxy)benzamide (ABT-199), or any pharmaceutically acceptable salt or hydrate thereof, or any stereoisomer or salt thereof.

[0136] In some specific embodiments, the anticancer agent according to this disclosure is ABT-199. ABT-199, or venetoclax, marketed under the trade names Venclexta and Venclyxto, is a drug used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML). Venetoclax is present in large quantities in CLL cancer cells, where it binds to the Bcl-2 protein, which helps the cells survive longer in the body and makes them resistant to cancer drugs. By binding to Bcl-2 and blocking its action, venetoclax causes cancer cell death, thereby slowing disease progression. Venetoclax is the first selective BCL2 inhibitor to be approved for routine clinical practice, specifically in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). The systematic name (IUPAC) of ABT-199 is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-l-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide (C45H50C1N7O7S, CAS number: 1257044-40-8). The molecular weight of ABT-199 is 868.45 g / mol.

[0137] In some further embodiments, the inhibitor of Bcl2 viability-promoting protein or BH3 mimetic compound is 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-l-en-1-yl]methyl}pi pci azin-1-yl)-N-(4-{[(2R)-4-(morpholine-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-l-sulfonyl)-benzamide (ABT-263), or any pharmaceutically acceptable salt or hydrate thereof, or any stereoisomer or salt thereof.

[0138] In some specific embodiments, the anticancer agent according to this disclosure is ABT-263. The systematic name (IUPAC) of ABT-263 is 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}pipcrazin-l-yl)-N-(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide(C 47 H 55 It is ClF3N5O6S3 (CAS number: 923564-51-6). The molecular weight of ABT-263 is 974.61 g / mol.

[0139] In some further embodiments, the inhibitor of Bcl2 viability-promoting protein or the BH3 mimetic compound is 2-(2-((3,5-dimethyl-1H-pyrrole-2-yl)methylene)-3-methoxy-2H-pyrrole-5-yl)-1H-indole (GX15-070), or any pharmaceutically acceptable salt or hydrate thereof, or any stereoisomer or salt thereof.

[0140] In some specific embodiments, the anticancer agent according to this disclosure is GX15-070 or ovatocrax. GX15-070 or ovatocrax is a drug for the treatment of various types of cancer. Ovatocrax is an inhibitor of the Bcl-2 family of proteins. This inhibition induces apoptosis in cancer cells and inhibits tumor growth. The systematic name (IUPAC) of GX15-070 is 2-(2-((3,5-dimethyl-1H-pyrrole-2-yl)methylene)-3-methoxy-2H-pyrrole-5-yl)-1H-indole(C 20 H 19 It is N3O (CAS number: 803712-7-6). The molecular weight of GX15-070 is 317.392 g / mol.

[0141] In some further embodiments, the inhibitor of Bcl2 viability-promoting protein or BH3 mimetic compound is 3-[l-(l-adamantylmethyl)-5-methylpyrazole-4-yl]-6-[8-(l,3-benzothiazole-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyridine-2-carboxylic acid (A-1331852), or any pharmaceutically acceptable salt or hydrate thereof, or any stereoisomer or salt thereof.

[0142] In some specific embodiments, the anticancer agent according to this disclosure is A-1331852. A-1331852 is a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. The systematic (IUPAC) name of A-1331852 is 3-[l-(l-adamantylmethyl)-5-methylpyrazole-4-yl]-6-[8-(l,3-benzothiazole-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-yl]pyridine-2-carboxylic acid (C 38 H 38 It is N6O3S (CAS number: 1430844-80-6). The molecular weight of A-1331852 is 658.27 g / mol.

[0143] In some embodiments, the anticancer agents according to the present invention are anti-autophagy agents. The term "anti-autophagy agent," known in the art, refers to a drug that interferes with the autophagy process, i.e., the regulated destructive mechanism of cells that breaks down unwanted or dysfunctional components. In contrast, an anti-autophagy agent is a compound that interferes with or inhibits the autophagy process, which may have therapeutic significance in certain diseases. Non-limiting examples of anti-autophagy agents include chloroquine and hydroxychloroquine, bafilomycin A1, spoutin-1, woltmannin, doxorubicin, or bleomycin.

[0144] In some embodiments, the anticancer agents according to this disclosure are biological agents. In the context of cancer treatments known in the art (sometimes called “immunotherapy”), the term “biological agent” involves the use of a living organism, a substance derived from a living organism, or a laboratory-produced version of such a substance for the treatment of a disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body’s immune system to act against cancer cells. Biological therapies that interfere with specific molecules involved in tumor growth and progression are also called targeted therapies.

[0145] In some embodiments, the anticancer agents according to this disclosure are anti-angiogenic agents. The term “anti-angiogenic factor” as it is known in the art refers to a drug that interferes with the process of angiogenesis, i.e., the formation of new blood vessels. Anti-angiogenic agents are a type of targeted therapy that uses a drug or other substance to stop a tumor from creating new blood vessels that it needs to continue to grow.

[0146] In some embodiments, the anticancer agents according to this disclosure are tyrosine kinase inhibitors. The term “tyrosine kinase inhibitor,” as known in the art, refers to a drug that inhibits tyrosine kinase. Tyrosine kinase is an enzyme involved in the activation of many proteins through signal transduction cascades. Proteins are activated by the addition of phosphate groups to the protein (phosphorylation), which is the step inhibited by tyrosine kinase inhibitors.

[0147] In some embodiments, at least one cyclic peptide of the method disclosed herein does not increase the level of bilirubin in the subject.

[0148] In some specific embodiments, at least one cyclic peptide of the method disclosed herein does not increase the level of bilirubin in the blood of the subject.

[0149] In some specific embodiments, the cyclic peptide of the method of the disclosure maintains the bilirubin level in the subject. In some specific embodiments, the cyclic peptide of the method of the disclosure does not change (or alter) the bilirubin level in the subject.

[0150] In some specific embodiments, the cyclic peptide of the method disclosed herein maintains the bilirubin level in the blood of the subject.

[0151] In some specific embodiments, the cyclic peptide of the method of this disclosure does not alter (or modify) the bilirubin level in the blood of the subject.

[0152] For example, a cyclic peptide comprising the amino acid sequence shown by Sequence ID No. 1 (or any one of Sequence IDs No. 2-10) may be administered by any route of administration known to those skilled in the art, such as intravenous (iv), or by any further appropriate route including intraperitoneal, subcutaneous, transdermal, topical, intramuscular, intra-articular, subconjunctival, or mucosal administration, such as oral, intranasal, or intraocular administration.

[0153] Cyclic peptides as defined herein, or any derivative thereof, may be administered in an “effective dose” necessary to achieve the desired therapeutic outcome. The “effective dose” is determined by the severity of the disease, in addition to the therapeutic objective, the route of administration, and the patient’s overall condition (age, sex, weight, and other considerations known to the attending physician). An effective dose for this use is generally in the range of 0.001 to 1000 mg / kg.

[0154] In some embodiments, the effective amount or effective dosage of the cyclic peptide of the present invention may refer to a dosage of 1 mg / m 2 ~500 mg / m 2 In some specific embodiments, the dosage may be 10 mg / m 2 or 12 mg / m 2 or 24 mg / m 2 or 48 mg / m 2 or 96 mg / m 2 or 100 mg / m 2 or 110 mg / m 2 or 120 mg / m 2 or 130 mg / m 2 or 140 mg / m 2 or 150 mg / m 2 or 160 mg / m 2 or 170 mg / m 2 or 180 mg / m 2 or 190 mg / m 2 or 192 mg / m 2 or 194 mg / m 2 or 196 mg / m 2 or 198 mg / m 2 or 200 mg / m 2 or 300 mg / m 2 or 400 mg / m 2 or 500 mg / m 2 In some embodiments, the effective dosage may be administered to the patient or subject as needed once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times a week.

[0155] In some embodiments, the effective dosage is administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times a week to the patient or subject as needed.

[0156] In some specific embodiments, the effective dosage of the cyclic peptide of the present disclosure is 192 mg / m 2 In some further embodiments, the effective dosage of the cyclic peptide of the present disclosure is 192 mg / m 2 and is administered three times a week to the patient or subject as needed. In some other embodiments, the effective dosage of the cyclic peptide of the present disclosure is 192 mg / m 2It is administered twice weekly to patients or subjects who require it. In some other embodiments, the effective dose of the cyclic peptide of this disclosure is 192 mg / m². 2 It is administered once a week to patients or subjects who require it.

[0157] In yet another aspect, the Disclosure provides a cyclic peptide, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, or any composition comprising the same, for use in a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject requiring such treatment, prevention, improvement, reduction or delaying the onset of such disorder, comprising the step of administering a therapeutically effective amount of a cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1.

[0158] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises n PEG moieties, the peptide having the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) (wherein n is the number of PEG moieties and is an integer from 1 to 10).

[0159] In some embodiments, n is 1, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 2.

[0160] In some embodiments, the cyclic peptide is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 3.

[0161] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 4.

[0162] In some embodiments, the cyclic peptide for use according to the present disclosure further comprises n sarcosine residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)) (wherein n is the number of Sar residues, and is an integer from 1 to 10).

[0163] In some embodiments, n is 1, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 5.

[0164] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 6.

[0165] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 7.

[0166] In some embodiments, the cyclic peptide for use in accordance with this disclosure comprises the amino acids shown by SEQ ID NO: 8.

[0167] In some embodiments, the cyclic peptide for use according to this disclosure further comprises n glycine (Gly) residues, and the peptide has the structure:cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)) (wherein n is the number of Gly residues, an integer from 1 to 10).

[0168] In some embodiments, n is 3, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 9.

[0169] In some embodiments, n is 5, and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO: 10.

[0170] In some embodiments, the peptides of this disclosure are directly or indirectly bound or conjugated to at least one therapeutic compound.

[0171] In some embodiments, at least one cyclic peptide for use in accordance with this disclosure is as defined in the embodiments described in detail above.

[0172] In some embodiments, the cyclic peptide for use in accordance with this disclosure involves administering a composition comprising at least one cyclic peptide as defined in the embodiments described in detail above.

[0173] In some embodiments, the composition is a pharmaceutical composition, and optionally further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

[0174] In some embodiments, the cyclic peptide for use in accordance with this disclosure further includes being administered to target at least one additional anticancer agent.

[0175] In some embodiments, the proliferative disorder is at least one of neuroblastoma, breast cancer, metastatic colorectal cancer, KRAS-mutated cancer, mCRC mtKRAS cancer, and / or melanoma. Further proliferative disorders related to cyclic peptides for use in accordance with this disclosure are defined in the preceding embodiments described above.

[0176] In some embodiments, the cyclic peptides for use according to this disclosure do not increase bilirubin levels in the subject.

[0177] In some specific embodiments, the cyclic peptides for use in accordance with this disclosure do not increase the level of bilirubin in the blood of the subject.

[0178] In some specific embodiments, the cyclic peptide for use in accordance with this disclosure maintains the level of bilirubin in the subject. In some specific embodiments, the cyclic peptide of the method of this disclosure does not alter (or modify) the level of bilirubin in the subject.

[0179] In some specific embodiments, the cyclic peptide for use according to this disclosure maintains the bilirubin level in the blood of the subject.

[0180] In some specific embodiments, the cyclic peptides for use in accordance with this disclosure do not alter (or modify) the bilirubin levels in the blood of the subject. In further embodiments, this disclosure provides a combination composition comprising at least one cyclic peptide or any functional derivative thereof (the amino acid residues of the peptide are D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown in SEQ ID NO: 1, and at least one anticancer agent or any pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the combination composition optionally comprises at least one pharmaceutically acceptable carrier, diluent, excipient, and / or additive.

[0182] In some embodiments, at least one cyclic peptide of the combination composition of the present disclosure is as defined in the embodiments described in detail above.

[0183] In some embodiments, at least one anticancer agent may be at least one of doxorubicin, taxol, cisplatin, a Bcl2 inhibitor, an anti-PDL1, and / or an anti-PD1. Further relevant anticancer agents are as defined in the earlier embodiments of this disclosure.

[0184] In some embodiments, the cyclic peptides of the combination compositions of the present disclosure can not increase bilirubin levels upon administration (e.g., to a target requiring it). In some specific embodiments, the cyclic peptides of the combination compositions of the present disclosure can maintain bilirubin levels upon administration (e.g., to a target requiring it). In some embodiments, the cyclic peptides of the combination compositions of the present disclosure can not (change or alter) bilirubin levels upon administration (e.g., to a target requiring it).

[0185] In some embodiments, the combination compositions of the present disclosure are intended for use in methods for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

[0186] In a further embodiment, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject requiring such treatment, comprising the steps of administering a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof (where the amino acid residues of the peptide are D-amino acid residues), at least one anticancer agent, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0187] In some embodiments, at least one cyclic peptide of the method of the present disclosure is as defined in the preceding embodiments above.

[0188] In some embodiments, at least one anticancer agent may be at least one of doxorubicin, taxol, cisplatin, a Bcl2 inhibitor, an anti-PDL1, and / or an anti-PD1. Further relevant anticancer agents are as defined in the earlier embodiments of this disclosure.

[0189] In some embodiments, at least one cyclic peptide of the method disclosed herein does not increase the level of bilirubin in the subject.

[0190] In some specific embodiments, at least one cyclic peptide of the method disclosed herein does not increase the level of bilirubin in the blood of the subject.

[0191] In some specific embodiments, the cyclic peptide of the method of the disclosure maintains the bilirubin level in the subject. In some specific embodiments, the cyclic peptide of the method of the disclosure does not change (or alter) the bilirubin level in the subject.

[0192] In some specific embodiments, the cyclic peptide of the method disclosed herein maintains the bilirubin level in the blood of the subject.

[0193] In some specific embodiments, the cyclic peptide of the method of this disclosure does not alter (or modify) the bilirubin level in the blood of the subject.

[0194] In another aspect, this disclosure is: (a) at least one cyclic peptide or any functional derivative thereof comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, and at least one anticancer agent or a pharmaceutically acceptable salt thereof, wherein the amino acid residues of the peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, and optionally included in the first dosage form. (b) A kit comprising at least one anticancer agent, which is optionally included in a second dosage form.

[0195] In some embodiments, at least one anticancer agent may be at least one of doxorubicin, taxol, cisplatin, a Bcl2 inhibitor, an anti-PDL1, and / or an anti-PD1. Further relevant anticancer agents are as defined in the earlier embodiments of this disclosure.

[0196] In some embodiments, at least one cyclic peptide of the kit of this disclosure is as defined in the preceding embodiments above.

[0197] In some embodiments, the cyclic peptides of the kits of this disclosure can be used without increasing bilirubin levels upon administration (e.g., to a target requiring attention). In some specific embodiments, the cyclic peptides of the kits of this disclosure can be used to maintain bilirubin levels upon administration (e.g., to a target requiring attention). In some embodiments, the cyclic peptides of the kits of this disclosure can be used without altering or changing bilirubin levels upon administration (e.g., to a target requiring attention).

[0198] In some embodiments, the kits of the present disclosure are intended for use in methods for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder in subjects requiring such treatment.

[0199] In a further embodiment, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject exhibiting high bilirubin levels, comprising the step of administering to the subject a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0200] In some embodiments, subjects exhibiting high levels of bilirubin suffer from at least one disease and / or condition associated with high bilirubin levels.

[0201] In another aspect, the present disclosure provides a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, the method comprising administering to the subject a therapeutically effective amount of at least one cyclic peptide (where the amino acid residues of the peptide are D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

[0202] In some embodiments, at least one agent is for treating at least one disease or condition associated with high bilirubin levels.

[0203] Bilirubin is a yellowish substance formed in the liver during the normal breakdown of red blood cells. It is a waste product produced when hemoglobin, the oxygen-carrying molecule of red blood cells, is broken down. Bilirubin is then released into the bloodstream and eventually eliminated from the body via bile, a fluid produced by the liver that aids in digestion. In safety studies, blood bilirubin levels are often measured as part of liver function tests or a comprehensive metabolic panel. Elevated levels of bilirubin in the blood, a condition known as hyperbilirubinemia, can indicate liver disease such as hepatitis or cirrhosis, or other conditions that affect the liver's ability to effectively process bilirubin. It can also be a sign of red blood cell dysfunction or bile duct obstruction.

[0204] The normal range of bilirubin levels in humans can vary slightly depending on the laboratory and the method used for measurement. However, generally, normal total bilirubin levels in adults are typically in the range of 0.2 to 1.2 milligrams (mg / dL) per deciliter or 3.4 to 20.5 micromoles (μmol / L) per liter.

[0205] Bilirubin levels can be further subdivided into two main types: unconjugated (indirect) bilirubin and conjugated (direct) bilirubin. Unconjugated (indirect) bilirubin is a form of bilirubin that is not water-soluble and binds to albumin in the bloodstream. Normal levels of unconjugated bilirubin are typically in the range of 0.2–0.8 mg / dL. Conjugated (direct) bilirubin is a form of bilirubin that has been processed by the liver and is water-soluble. Normal levels of conjugated bilirubin are usually less than 0.3 mg / dL.

[0206] In some embodiments, the bilirubin level refers to the bilirubin level in a human subject. In some embodiments, the bilirubin level in a human subject (e.g., in the blood of the human subject) may refer to the total bilirubin level. In some embodiments, a high total bilirubin level (e.g., in the blood of the human subject) may exceed 1 mg / dL. In some further embodiments, high bilirubin levels in human subjects (e.g., in the blood of human subjects) may exceed 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0 mg / dL. In some specific embodiments, high total bilirubin levels in human subjects (e.g., in the blood of human subjects) may exceed 1.2 mg / dL.

[0207] In some embodiments, high total bilirubin levels in human subjects (e.g., in the blood of human subjects) may exceed 20 micromoles (μmol / L) per liter. In some further embodiments, high total bilirubin levels in human subjects (e.g., in the blood of human subjects) may exceed 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 μmol / L. In some specific embodiments, high total bilirubin levels in human subjects (e.g., in the blood of human subjects) may exceed 20.5 μmol / L.

[0208] In some embodiments, bilirubin levels in human subjects (e.g., in the blood of human subjects) may refer to unconjugated (indirect) bilirubin. In some embodiments, high unconjugated (indirect) bilirubin levels in human subjects (e.g., in the blood of human subjects) may be 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, The levels may exceed 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0 mg / dL. In some specific embodiments, high levels of unconjugated (indirect) bilirubin in human subjects (e.g., in the blood of human subjects) may exceed 0.8 mg / dL.

[0209] In some other embodiments, bilirubin levels in human subjects (e.g., in the blood of human subjects) may refer to conjugated (direct) bilirubin. In some specific embodiments, the amount of highly conjugated (direct) bilirubin in human subjects (e.g., in the blood of human subjects) may exceed 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, and 5.0 mg / dL. In some embodiments, the amount of highly conjugated (direct) bilirubin in human subjects (e.g., in the blood of human subjects) may be greater than 0.3 mg / dL.

[0210] In some embodiments, at least one cyclic peptide of the method of the present disclosure is as defined in the preceding embodiments above.

[0211] In some embodiments, the subjects suffer from at least one disease and / or condition associated with high bilirubin levels.

[0212] In some embodiments, the at least one disease and / or condition associated with high bilirubin levels is at least one of the following: liver disease, blood disorders, biliary disorders, and / or hereditary disorders.

[0213] In some further embodiments, the disease and / or condition associated with high bilirubin levels may be at least one of jaundice, liver disease, hemolytic anemia, biliary disorders, and / or hereditary disorders.

[0214] In some embodiments, the disease and / or condition associated with high bilirubin levels may be jaundice. Jaundice is a condition characterized by yellowing of the skin and whites of the eyes due to high levels of bilirubin in the blood. It can occur as a result of various underlying conditions, including liver diseases such as hepatitis, cirrhosis, or liver cancer, as well as conditions affecting the bile ducts, such as gallstones or bile duct obstruction.

[0215] In some embodiments, the disease and / or condition associated with high bilirubin levels may be liver disease (or hepatic disease). Various liver diseases can cause impaired bilirubin metabolism and clearance, leading to elevated blood bilirubin levels. In some embodiments, the liver disease may be at least one of hepatitis (inflammation of the liver), cirrhosis (scarring of the liver), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and / or liver cancer.

[0216] In some embodiments, the disease and / or condition associated with high bilirubin levels may be hemolytic anemia. In hemolytic anemia, the breakdown of red blood cells is accelerated, leading to elevated bilirubin levels. Conditions that can cause hemolytic anemia include autoimmune disorders such as autoimmune hemolytic anemia, infections, drug therapies, and genetic disorders such as sickle cell anemia or thalassemia.

[0217] In some embodiments, the disease and / or condition associated with high bilirubin levels may be a biliary disorder. A biliary disorder refers to a condition that obstructs or impairs the flow of bile from the liver to the intestines, which can cause elevated bilirubin levels. This may include biliary obstruction due to gallstones, tumors, or strictures (narrowing of the bile ducts). In some embodiments, the biliary disorder may be at least one of the following: biliary obstruction, primary sclerosing cholangitis (PSC), congenital biliary atresia, common bile duct cyst, common bile duct cyst, or biliary duct stricture.

[0218] In some embodiments, the disease and / or condition associated with high bilirubin levels may be a hereditary disorder. In some embodiments, the hereditary disorder may be Gilbert's syndrome. Gilbert's syndrome is a relatively common hereditary disorder characterized by a mild elevation of bilirubin levels, particularly unconjugated bilirubin. It is usually benign and does not cause serious health problems, but it may cause intermittent jaundice.

[0219] In some embodiments, the hereditary disorder may be Dubin-Johnson syndrome. In some embodiments, the hereditary disorder may be Rotor syndrome. Dubin-Johnson syndrome and Rotor syndrome are rare hereditary disorders that affect bilirubin metabolism and excretion, resulting in elevated levels of bilirubin in the blood. Dubin-Johnson syndrome is characterized by chronic jaundice and hepatic pigment accumulation, while Rotor syndrome presents with similar symptoms but without hepatic pigment accumulation.

[0220] In some embodiments, the hereditary disorder may be Crigler-Nadjar syndrome. Crigler-Nadjar syndrome is a hereditary disorder characterized by the absence or deficiency of an enzyme called uridine diphosphate glucuronosyltransferase (UGT). This enzyme plays a crucial role in the liver's ability to process bilirubin, a waste product of red blood cells. In individuals with Crigler-Nadjar syndrome, the lack of functional UGT enzyme leads to an accumulation of unconjugated bilirubin in the blood, resulting in jaundice and potential neurological complications. In some embodiments, high bilirubin levels are caused by at least one of the following: medication, infection, and / or physiological factors.

[0221] In some embodiments, the drug that can cause high bilirubin levels may be at least one of the following: antibiotics (e.g., erythromycin, rifampin), antifungal agents (e.g., ketoconazole), antiviral agents (e.g., indinavir), and / or chemotherapeutic agents.

[0222] In some embodiments, the infection that may cause high bilirubin levels may be at least one of the following: viral hepatitis (e.g., hepatitis A, B, or C), bacterial infection or bacterial hepatitis affecting the liver (e.g., caused by Salmonella, Leptospira, or Brucellosis bacteria), and / or an inflammatory condition (e.g., cholangitis).

[0223] In some embodiments, physiological factors that may cause high bilirubin levels may be at least one of neonatal jaundice, fasting, dehydration, and / or strenuous physical exercise. In some embodiments, at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) may be at least one ursodeoxycholic acid (UDCA) or ursodiol, rifampicin, phenobarbital, and / or cholestyramine.

[0224] In some embodiments, at least one agent for treating high bilirubin levels (or at least one disease associated with high bilirubin levels) may be ursodeoxycholic acid (UDCA). Ursodeoxycholic acid (UDCA), or ursodiol, is a bile acid that is naturally produced in the body and is also available as a pharmaceutical product. It is commonly used to treat various liver diseases and conditions, as described above.

[0225] In some embodiments, at least one agent for treating high bilirubin levels (or at least one disease associated with high bilirubin levels) may be rifampicin. Rifampicin is an antibiotic that also possesses bile acid chelating properties. Rifampicin may be used off-label for certain conditions associated with elevated bilirubin levels, particularly Crigler-Nadjar syndrome and Gilbert's syndrome.

[0226] In some embodiments, at least one agent for treating high bilirubin levels (or at least one disease associated with high bilirubin levels) may be phenobarbital. Phenobarbital is a barbiturate drug used to treat certain liver conditions associated with elevated bilirubin levels, particularly unconjugated hyperbilirubinemia. It acts by increasing the activity of liver enzymes involved in bilirubin metabolism and excretion. Phenobarbital can be used to lower bilirubin levels and alleviate symptoms of jaundice in conditions such as Gilbert's syndrome or Crigler-Nadjar syndrome type II.

[0227] In some embodiments, at least one agent for treating high bilirubin levels (or at least one disease associated with high bilirubin levels) may be cholestyramine. Cholestyramine is a bile acid sequestering agent that binds to bile acids in the intestines, preventing their reabsorption and promoting their excretion in the feces. It is sometimes used to treat certain cholestatic liver diseases such as primary biliary cholangitis (PBC) or pregnancy-related intrahepatic cholestasis (ICP) to improve bile flow and reduce itching associated with elevated bilirubin levels.

[0228] In some embodiments, at least one agent for treating high bilirubin levels (or at least one disease associated with high bilirubin levels) may be N-acetylcysteine ​​(NAC). N-acetylcysteine ​​is a commonly used drug as a mucolytic and antidote for acetaminophen overdose. Its potential hepatoprotective effects and its ability to improve liver function in various liver diseases have also been studied. While NAC is not a direct treatment for high bilirubin levels, it may help mitigate liver damage and inflammation that may contribute to elevated bilirubin levels in certain conditions.

[0229] Further aspects of the present disclosure provide a combination composition comprising at least one cyclic peptide or any functional derivative thereof (where the amino acid residues of the peptide are D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, at least one agent or a pharmaceutically acceptable salt thereof for treating at least one disease and / or condition associated with high bilirubin levels, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0230] In some embodiments, the combination composition is intended for use in treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder in subjects exhibiting high bilirubin levels.

[0231] Further aspects of this disclosure are: (a) at least one cyclic peptide or any functional derivative thereof comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, and at least one anticancer agent or a pharmaceutically acceptable salt thereof, wherein the amino acid residues of the peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, and optionally included in the first dosage form. (b) at least one agent for treating at least one disease and / or condition associated with high bilirubin levels, which is optionally included in a second dosage form, We provide a kit that includes this.

[0232] In some embodiments, the kit is intended for use in treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder in subjects exhibiting high bilirubin levels.

[0233] In some embodiments, at least one cyclic peptide of the combination composition or kit referred to herein is as defined in the earlier aspects of this disclosure.

[0234] In some embodiments, at least one agent for treating high bilirubin levels (or for treating at least one disease associated with high bilirubin levels) is at least one ursodeoxycholic acid (UDCA) or ursodiol, rifampicin, phenobarbital and / or cholestyramine.

[0235] In some embodiments, the combination composition or kit is intended for use in subjects requiring a method for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

[0236] Further aspects of the present invention relate to a conjugate comprising a peptide having the amino acid sequence shown by Sequence ID No. 1 or any functional derivative thereof (where the amino acid residues of the peptide are D-amino acid residues) and doxorubicin having the following formula.

[0237] [ka]

[0238] An additional aspect of the present invention relates to a pharmaceutical composition comprising a conjugate and at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

[0239] In some embodiments, the pharmaceutical composition is intended for use in methods for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

[0240] Further aspects of the present disclosure provide a method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject requiring such treatment, comprising the step of administering a therapeutically effective amount of a conjugate.

[0241] In some embodiments, the conjugate is intended for use in a manner that treats, prevents, improves, reduces, or delays the onset of at least one proliferative disorder in a subject requiring it, the manner comprising the step of administering a therapeutically effective amount of the conjugate.

[0242] The term “treatment or prevention” refers to the entire range of therapeutically positive effects of administration to a subject, including inhibition, reduction, mitigation, and reduction of proliferative disorder symptoms or undesirable side effects of such proliferative disorder-related disorders. More specifically, treatment or prevention includes preventing or delaying the onset of a disease, preventing or delaying the onset of symptoms, and / or reducing the severity of such symptoms that have developed or are expected to develop. These further include improving existing symptoms, preventing further symptoms, and improving or preventing the underlying metabolic causes of symptoms.

[0243] As used herein, “disease,” “disorder,” “condition,” etc., are used interchangeably when relating to health, and each of these terms has an all-encompassing meaning.

[0244] This invention relates to the treatment of subjects or patients in need of treatment. “Patient” or “subject in need” means any organism that may be affected by the above-mentioned conditions and for which the treatment methods described herein are desired, and includes humans, livestock and non-livestock mammals, e.g., dogs and cats, cattle, monkeys, horses and mice, rodents, domestic birds, aquaculture, fish and exotic ornamental fish. It should be understood that the subject to be treated may also be any reptile or zoo animal. More specifically, the methods and compositions of the present invention are intended for mammals. “Mammalian subject” means any mammal for which the proposed treatment is desired, including humans, horses, dogs and cats, most specifically humans. It should be noted that, particularly in the case of non-human subjects, the methods of the present invention may be carried out by direct administration to the gastrointestinal tract of the subject in need, via injection, drinking water, feed, spray, or forced oral administration. In particular, in the case of human subjects, it should be further noted that administration of the compositions of the present invention to a patient includes both self-administration and administration to a patient by another person.

[0245] It should be noted that all embodiments described in relation to one aspect of this disclosure may be applicable to any other suitable aspect of this disclosure.

[0246] All definitions defined and used herein are understood to govern dictionary definitions, definitions in literature incorporated by reference, and / or the ordinary meanings of the defined terms.

[0247] As used herein, the term “approximately” indicates a value that can vary by up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20%, above or below the value mentioned, and the range of variation includes integer values, and where applicable, non-integer values ​​also constitute a continuous range. In some embodiments, the term “approximately” refers to ±10%.

[0248] The indefinite articles "a" and "an" used herein and in the claims should be understood to mean "at least one" unless explicitly stated otherwise. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple things unless explicitly stated otherwise by the context.

[0249] As used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements thus combined, i.e., elements that are sometimes conjunctive and sometimes disjunctive. Any multiple elements listed in “and / or” should similarly be interpreted as “one or more” of the elements thus combined. Other elements besides those specifically identified by the “and / or” clause may exist at their discretion, whether related to or unrelated to those specifically identified elements. Therefore, as a non-restrictive example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising,” could refer in one embodiment to A only (with optional inclusion of elements other than B), in another embodiment to B only (with optional inclusion of elements other than A), in yet another embodiment to both A and B (with optional inclusion of other elements), and so on.

[0250] Where used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as inclusive, that is, including at least one of multiple elements or lists of elements, but also including two or more, and optionally including additional unlisted items. Only terms that are explicitly indicated to the contrary, such as “one of ~” or “exactly one of ~” or, where used in the claims, “consisting of ~,” refer to including exactly one element of multiple elements or lists of elements. In general, where used herein, the terms “or” and “either,” “one of ~,” “one of ~,” or “exactly one of ~” or “essentially consisting of ~” shall be interpreted only as indicating an exclusive choice (i.e., “one or the other, but not both”) when preceded by a term of exclusivity, and where used in the claims, shall have the usual meaning as used in the field of patent law.

[0251] As used herein and in the claims, the phrase “at least one” with respect to a list of one or more elements means at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of every element specifically enumerated in the list of elements, nor excluding any combination of elements in the list of elements. This definition also allows for the presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to those specifically identified elements or not, at the discretion of the system. Therefore, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") may refer to, in one embodiment, at least one A including two or more of the optional A, and no B (or an optional element other than B); in another embodiment, at least one B including two or more of the optional B, and no A (or an optional element other than A); and in yet another embodiment, at least one A including two or more of the optional A, and at least one B including two or more of the optional B (and an optional element other than A).

[0252] Furthermore, unless explicitly stated otherwise, in any method claimed herein that includes two or more steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are enumerated.

[0253] Throughout this specification and the following examples and claims, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to be open-ended, meaning that they include but are not limited to them. Specifically, it should be understood that they include the integers or processes or groups of integers or processes mentioned, but not the exclusion of any other integers or processes or groups of integers or processes. As described in the United States Patent Office Manual of Patent Examining Procedures, only the transitional phrases “consisting of” and “consisting essentially of” are closed or semi-closed transitional phrases, respectively. More specifically, the terms “comprises,” “comprising,” “includes,” “including,” and “having,” and their conjugations, mean “including but not limited to.” The term "consisting of" means "including and limited to." The term "consisting essentially of" means that the composition, method, or structure may include additional components, steps, and / or parts, but only if the additional components, steps, and / or parts do not substantially alter the basic and novel features of the claimed composition, method, or structure.

[0254] It should be noted that various embodiments of the present invention may be presented in range form. It should be understood that range form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of the invention. Therefore, a range description should be considered to include all possible subranges specifically disclosed and the individual numerical values ​​within those ranges. For example, a range description such as 1–6 should be considered to specifically disclose subranges such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, and the individual numbers within those ranges, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is shown herein, it is understood to include any cited digits (fractions or integers) within the indicated range. The phrases "ranging / ranges between" the first indicated number and the second indicated number, and "ranging / ranges from" the first indicated number to the second indicated number, are used interchangeably herein and mean to include the first and second indicated numbers as well as all fractions and integers in between.

[0255] As used herein, the term “method” means a mode, means, technique and procedure for accomplishing a given task (including, but not limited to, modes, means, techniques and procedures known to practitioners of the chemical, pharmacological, biological, biochemical and medical fields, or readily developed from known modes, means, techniques and procedures).

[0256] For clarity, certain features of the Invention described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, various features of the Invention described in the context of a single embodiment for brevity may also be provided separately, in any preferred subcombination, or as suitable for any other described embodiment of the Invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments are inoperable without those elements.

[0257] The various embodiments and aspects of the present invention described herein above and claimed in the following claims section are supported by experiment in the following examples.

[0258] While disclosed and described herein, it should be understood that the present invention is not limited to the specific examples, processes, and compositions disclosed herein, and that such processes and compositions may be subject to some variation. It should also be understood that the scope of the present invention is limited only by the appended claims and their equivalents, and that the terms used herein are used solely for the purpose of describing specific embodiments and are not intended to limit them.

[0259] The following examples are representative examples of techniques used by the inventors when carrying out aspects of the present invention. While these techniques are illustrative of preferred embodiments for carrying out the present invention, it should be understood that those skilled in the art will recognize that many modifications can be made in consideration of this disclosure without departing from the spirit and intended scope of the invention. [Examples]

[0260] Without further detail, those skilled in the art will likely be able to make the most of the present invention using the description above. Therefore, the following preferred specific embodiments should be interpreted as merely illustrative and not to limit the present invention as described in the claims.

[0261] material: - Clear bottom black 96-well cell culture plate (Greiner 60-65590) - Cell culture medium: • 10% FBS (Biological Industries, catalog number 04-121-1A) • DMEM (Gibco, catalog number 41965) • 1 mM sodium pyruvate (Biological Industries) • 100 μg / ml penicillin and 100 pg / ml streptomycin (Biological Industries) • 250 ng / ml amphotericin B (Biological Industries) • 100 μg / ml of normosine (ant-nr-2 Invivogen) -Cell treatment medium 1: Cell culture medium + 5% mannitol (filtration after mannitol addition) - Cell treatment medium 2: Cell culture medium containing 2% FBS (instead of 10% FBS) + 5% mannitol, without phenol red (filtered after mannitol addition) - Cell culture medium for MTT: Cell culture medium that does not contain phenol red or FBS. -MTT assay kit (Cell Proliferation) (ab211091) -Cell lines: SH-SY5Y (ATCC(R) CRL-2266(TM)), MDA-MB-231(ATCC(R) HTB-26(TM)) For treatment: • Nerofe stock solution: Diluted to 3 mg / ml with 5% mannitol in DW. • Nerofe derivative 1-10 stock solution: Dilute in DMSO to a concentration of at least 6 mg / ml

[0262] Summary of the treatment regimen: Cells were treated either untreated or with 25 or 50 μg / ml of Nerofe or a Nerofe derivative on days 2 and 4 after seeding. An MTT assay was performed on day 5.

[0263] Procedure 1. Cells were seeded at 3000 cells / well in a clear-bottom black 96-well plate in 100 μl of growth medium. All unused wells were filled with 100 μl of medium. Blank cells were left without seeded wells. Incubation was for 24 hours. 2. The medium was removed. For untreated wells, only 100 μl of treatment medium 1 was added, and for treated wells, 100 μl of 25 or 50 μg / ml of Nerofe or Nerofe derivatives 1 - 10 were added to a total of 100 μl of treatment medium 1. Incubation was for 48 hours. 3. The medium was removed. For untreated wells, only 100 μl of treatment medium 2 was added, and for treated wells, 100 μl of 25 or 50 μg / ml of Nerofe or Nerofe derivatives 1 - 10 were added to a total of 100 μl of treatment medium 2. Incubation was for 24 hours. 4. The medium was removed. 50 μl of MTT and 50 μl of cell medium for MTT were added. Incubation was carried out in an incubator for 3 hours. 5. The wells were emptied and 150 μl of solvent was added. Shaking was for 15 minutes. Reading was performed at 590 OD using a microplate reader.

[0264] Preparation of dTCApF Peptide or NEROFE™ and Its Derivatives The peptide dTCApF or NEROFE™ (both terms are used interchangeably herein and refer to the same peptide as above) is a peptide 14 amino acid residues long, with all amino acid residues in the D configuration, and has an amino acid sequence of Trp Trp Thr Phe Phe Leu Pro Ser Thr Leu Trp Glu Arg Lys (or, in one-letter code, WWTFFLPSTLWERK, represented by SEQ ID NO: 1). Derivatives of Nerofe are described in Table 1 below.

[0265] The Nerofe derivatives listed in Table 1 below were obtained by covalently bonding doxorubicin (peptide 1), or the PEG moiety (peptides 2, 3, and 4), or a sarcosine residue (peptides 5, 6, and 7), or a glycine residue (peptide 9 or 10) to D-Trp (N-terminus) and D-Lys (C-terminus) to form a ring-closing molecule. Further Nerofe derivatives (peptide 8) were obtained by cyclization of the Nerofe peptide without any additions.

[0266] Example 1 Preparation of several derivatives of Nerofe D peptide Prepare several derivatives of the D-peptide called "Nerofe" and list them in Table 1 below. Nerofe derivative 1 (Compound ID 1) was obtained by covalently bonding the compound doxorubicin to the N-terminus of Nerofe. Nerofe derivative 2 (Compound ID 2 represented by SEQ ID NO: 2) was obtained by adding one polyethylene glycol (PEG) moiety to the lysine residue of Nerofe (PEGylation) and cyclizing it. Nerofe derivative 3 (Compound ID 3 represented by SEQ ID NO: 3) was obtained by adding three PEG units to the lysine residue of Nerofe and cyclizing it. Nerofe derivative 4 (Compound ID 4 represented by SEQ ID NO: 4) was obtained by adding five PEG units to the lysine residue of Nerofe and cyclizing it. Nerofe derivative 5 (Compound ID 5 represented by SEQ ID NO: 5) was obtained by adding one sarcosine residue to the lysine residue of Nerofe and cyclizing it. Nerofe derivative 6 (Compound ID 6 represented by SEQ ID NO: 6) was obtained by adding three sarcosine residues to the lysine residue of Nerofe and cyclizing it. Nerofe derivative 7 (Compound ID 7 represented by SEQ ID NO: 7) was obtained by adding five sarcosine residues to the lysine residue of Nerofe and cyclizing it. Nerofe derivative peptide 8 (Compound ID 8 represented by SEQ ID NO: 8) was obtained by cyclizing Nerofe. Nerofe derivative peptide 9 represented by SEQ ID NO: 9 was obtained by adding three glycine residues to the lysine residue of Nerofe and cyclizing it. Nerofe derivative peptide 10 represented by SEQ ID NO: 10 was obtained by adding five glycine residues to the lysine residue of Nerofe and cyclizing it.

[0267] The cyclization of the Nerofe derivative bonded to the PEG residue was performed as follows: head-to-tail lactam ring formation was used. Briefly, CTC resin (chlorotrityl chloride) was used for synthesis, and Fmoc(9-fluorenylmethyloxycarbonyl)-PEG(n) was first coupled to the resin (c-terminus). Solid-phase synthesis was continued. Next, the peptide was cleaved from the resin using HFIP (hexafluoroisopropanol) / DCM (dichloromethane) to create a head-to-tail lactam ring between PEG(n) and D-Trp. Finally, cleavage was performed using a strong acid to deprotect the amino acid side chains.

[0268] [Table 1]

[0269] Example 2 The effect of Nerofe and its derivatives on inducing cell death in SHSY5Y cells. The effects of Nerofe and its derivatives on the cell viability of SHSY5Y cells (human neuroblastoma cell line) were investigated. As shown in Figure 1, covalent bonding of doxorubicin to Nerofe (Nerofe derivative 1) was not effective in inducing cell death, but the effect on inducing cell death became more significant as the number of PEG units in the cyclic peptide was added to Nerofe (Nerofe derivatives 2, 3, and 4). The addition of sarcosine residues provided a similar effect on inducing cell death as the original Nerofe peptide.

[0270] Example 3 Effects of Nerofe and its derivatives on inducing cell death in MDA231 cells The effects of Nerofe and its derivatives on the cell viability of MDA231 cells (epithelial human breast cancer cell line) were tested. As shown in Figure 1, covalent bonding of doxorubicin to Nerofe (Nerofe derivative 1) was not effective in inducing cell death, but the effect on inducing cell death became more significant as the number of PEG units in the cyclic peptide was added to Nerofe (Nerofe derivatives 2, 3, and 4), and these effects were even greater than those of the original Nerofe. Similarly, the effect on inducing cell death became more significant as the number of sarcosine (N-methylglycine) residues in the cyclic peptide was added to Nerofe (Nerofe derivatives 5, 6, and 7), but the addition of 3 and 5 sarcosine residues resulted in better effects than the original Nerofe peptide.

[0271] Example 4 Effects of Nerofe and its derivatives on inducing cell death in SKBR3 cells The effects of Nerofe and its derivatives on the cell viability of SKBR3 cells (human breast cancer cell line) were tested. As shown in Figure 1, covalent bonding of doxorubicin to Nerofe (Nerofe derivative 1) was not effective in inducing cell death, but the addition of 1 to 5 PEG units to the cyclic peptide provided a greater effect than the original Nerofe peptide (Nerofe derivatives 2, 3, and 4). The addition of one sarcosine residue to the cyclic peptide was not effective (Nerofe derivative 5), but the addition of 3 and 5 sarcosine residues provided a greater effect than the original Nerofe peptide (Nerofe derivatives 6 and 7).

[0272] Example 5 Effects of Nerofe and its derivatives on tumor volume in mice injected with CT26 cells Balc / C mice (5 weeks old, body weight: 20g) were obtained from Harlan Laboratories Ltd. (Israel). 100,000 CT26 cells (metastatic colorectal cancer, KRAS variant, mCRC mtKRAS) were subcutaneously injected into the mice. The largest tumor size was 50mm. 3After reaching a certain stage (7-10 days after injection), treatment with standard Nerofe and cyclic Nerofe derivative 3 (compound ID 3, indicated by SEQ ID NO: 3) was initiated. The mice were divided into four different groups of seven mice each: Group 1 - untreated group, 5% mannitol IP injection once a week; Group 2 - treated with standard Nerofe (15 mg / kg, three times a week); Group 3 - treated with cyclic Nerofe derivative 3 (15 mg / kg, three times a week).

[0273] As shown in Figure 2, the rate of increase in mouse tumor volume decreased after treatment with Nerofe. However, the rate of increase in mouse tumor volume decreased further after treatment with cyclic Nerofe derivative 3. Therefore, cyclic Nerofe derivative 3 appears to be more efficient than conventional Nerofe.

[0274] The effects of additional Nerofe derivatives listed in Table 1 on tumor volume in mice injected with CT26 cells will also be evaluated.

[0275] Example 6 Effects of Nerofe and its derivatives on total bilirubin levels in mice Total bilirubin (mg / dl) levels were evaluated in Balb / c mice treated with IP injections of either standard Nerofe (10 mg / kg) or cyclic Nerofe derivative 3 (10 mg / kg) three times a week. Total bilirubin levels (mg / dl) were measured at the end of the six injections, two weeks later. The control group was injected with a 5% mannitol solution. As shown in Table 2 below, bilirubin levels increased in mice treated with standard Nerofe, but appeared to remain unchanged in mice treated with cyclic Nerofe derivative 3.

[0276] We will also evaluate the total bilirubin (mg / dl) levels in Balb / c mice that received IP injections of the additional Nerofe derivatives listed in Table 1 three times a week.

[0277] [Table 2]

[0278] Example 7 Effect of the combination of Nerofe and its derivatives with Bcl2 inhibitors in a mouse model Balc / C mice (5 weeks old, body weight: 20 g) are obtained from Harlan Laboratories Ltd. (Israel). 100,000 CT26 cells (metastatic colorectal cancer, KRAS mutant, mCRC mtKRAS) are subcutaneously injected into the mice. Treatment is started after the tumor size reaches 50 mm 3 in its maximum dimension (7 - 10 days after injection). The mice are divided into the following different groups of mice. - Group A - Control - Group B - Nerofe (15 mg / kg, intraperitoneal (IP), 3 times a week - Group C - Cyclic Nerofe derivative 3 (15 mg / kg, 3 times a week) - Group D - ABT - 737, IP, 3 times a week - Group E - ABT - 199 (venetoclax), IP, 3 times a week - Group F - ABT - 263 (navitoclax), IP, 3 times a week, IP, 3 times a week - Group G - GX15 - 070 (obatoclax), IP, 3 times a week, IP, 3 times a week - Group H - A - 1331852, IP, 3 times a week, IP, 3 times a week - Group I - Nerofe, IP, 3 times a week + ABT - 737, IP, 3 times a week - Group J - Nerofe, IP, 3 times a week + ABT - 199 (venetoclax), IP, 3 times a week - Group K - Nerofe, IP, 3 times a week + ABT - 263 (navitoclax), IP, 3 times a week - Group L - Nerofe, IP, 3 times a week + GX15 - 070 (obatoclax), IP, 3 times a week - Group M - Nerofe, IP, 3 times a week + A - 1331852 (obatoclax), IP, 3 times a week. - Group N - Cyclic Nerofe derivative 3, IP, 3 times a week + ABT - 737, IP, 3 times a week - Group O - Cyclic Nerofe derivative 3, IP, 3 times a week + ABT - 199 (venetoclax), IP, 3 times a week -Group P-cyclic Nerofe derivative 3, IP, 3 times a week + ABT-263 (Navitoclax), IP, 3 times a week -Group Q-cyclic Nerofe derivative 3, IP, 3 times a week + GX15-070 (Obatoclax), IP, 3 times a week -Group R-cyclic Nerofe derivative 3, IP, 3 times a week + A-1331852 (Obatoclax), IP, 3 times a week.

[0279] The body weight of the mice is measured twice a week, and the tumor volume is also measured twice a week.

[0280] The effects of additional Nerofe derivatives, detailed in Table 1, in combination with the above-mentioned Bcl2 inhibitors on tumor volume in mice injected with CT26 cells will also be evaluated.

[0281] Example 8 Combinations of Nerofe and its derivatives with chemotherapeutic agents such as doxorubicin and / or cisplastin. Balc / C mice (5 weeks old, body weight: 20g) were obtained from Harlan Laboratories Ltd. (Israel). 100,000 CT26 cells (metastatic colorectal cancer, KRAS variant, mCRC mtKRAS) were subcutaneously injected into the mice. The tumor size reached a maximum of 50mm. 3 Treatment was initiated after reaching a certain stage (7-10 days after injection). The mice were divided into the following different groups. -Group A-Control -Group B-Nerofe (15 mg / kg, intraperitoneal (IP), 3 times weekly) - Group C-cyclic Nerofe derivative 3 (15 mg / kg, 3 times a week) -Group D- Doxorubicin, IP, once weekly (2 mg / kg) - Group E-cisplatin, IP, 20 mg / kg, once a week, IP, three times a week - Group F-Nerofe, IP, 3 times a week + Doxorubicin, IP, 1 time a week (2 mg / kg) - Group G-Nerofe, IP, 3 times a week + cisplatin, IP, 20 mg / kg, once a week - Group H-cyclic Nerofe derivative 3, IP 3 times a week + Doxorubicin, IP, once a week (3 mg / kg) -Group I-cyclic Nerofe derivative 3, IP, 3 times a week + cisplastin, IP, 20 mg / kg, once a week

[0282] The body weight of the mice is measured twice a week, and the tumor volume is also measured twice a week.

[0283] The effects of additional Nerofe derivatives, detailed in Table 1, in combination with the above-mentioned chemotherapeutic agents on tumor volume in mice injected with CT26 cells will also be evaluated.

[0284] Example 9 Combinations of Nerofe and its derivatives with immune checkpoint inhibitors such as anti-PDL1 and / or anti-PD1 monoclonal antibodies The effects of conventional Nerofe or cyclic Nerofe derivatives (listed in Table 1) in combination with anti-PD-L1 antibodies or anti-PD1 antibodies will be investigated in a mouse model for melanoma antibodies, as detailed below.

[0285] C57B16 mice were inoculated with 200,000 B16 cells per mouse via SC. Tumors were 50 mm in size. 3 If the volume exceeds a certain limit, the mice are randomly divided into several groups as follows: the "control" group is treated with 5% mannitol, the "anti-PDL1 antibody" group is treated with anti-PDL1 antibody (BX cells), the "anti-PDL1 antibody + Nerofe" group is treated with Nerofe and anti-PDL1 antibody, the "anti-PDL1 antibody + cyclic Nerofe derivative 3" and "anti-PD1 antibody" groups are treated with anti-PD1 antibody, the "anti-PD1 antibody + Nerofe" group is treated with Nerofe and anti-PD1 antibody, and the "anti-PD1 antibody + cyclic Nerofe derivative 3" group is treated with anti-PD1 antibody. Nerofe and cyclic Nerofe derivative 3 are administered at 1 mg / kg three times a week, anti-PDL1 antibody is administered at 20 mg / kg twice a week, and anti-PD1 antibody is administered at 1 mg / kg once every two weeks.

[0286] Next, we evaluate the changes in tumor volume in mice.

[0287] The effects of additional Nerofe derivatives, detailed in Table 1, in combination with the anti-PDL1 and anti-PD1 antibodies described above, on changes in tumor volume in mice injected with B16 cells will also be evaluated.

Claims

1. A cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by Sequence ID No. 1, or any functional derivative thereof, wherein the amino acid residues of the peptide are D-amino acid residues.

2. The cyclic peptide according to claim 1, further comprising n polyethylene glycol (PEG) moieties, wherein the peptide has the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(PEG)) (wherein n is the number of PEG moieties and is an integer from 1 to 10).

3. The cyclic peptide according to claim 2, wherein n is 1 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

2.

4. The cyclic peptide according to claim 2, wherein n is 3 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

3.

5. The cyclic peptide according to claim 2, wherein n is 5 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

4.

6. The cyclic peptide according to claim 1, further comprising n sarcosine (Sar) residues, wherein the peptide has the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Sar)) (wherein n is the number of Sar residues and is an integer from 1 to 10).

7. The cyclic peptide according to claim 6, wherein n is 1 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

5.

8. The cyclic peptide according to claim 6, wherein n is 3 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

6.

9. The cyclic peptide according to claim 6, wherein n is 5 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

7.

10. The cyclic peptide according to claim 1, comprising the amino acid shown by SEQ ID NO:

8.

11. The cyclic peptide according to claim 1, further comprising n glycine (Gly) residues, wherein the peptide has the structure: cyclo(Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys-n(Gly)) (wherein n is the number of Gly residues and is an integer from 1 to 10).

12. The cyclic peptide according to claim 11, wherein n is 3 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

9.

13. The cyclic peptide according to claim 11, wherein n is 5 and the cyclic peptide comprises the amino acid sequence shown by SEQ ID NO:

10.

14. The cyclic peptide according to any one of claims 1 to 13, wherein the peptide is directly or indirectly bound or conjugated to at least one therapeutic compound.

15. A composition comprising at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by Sequence ID No. 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and optionally the composition further comprises at least one carrier, diluent, excipient, additive, stabilizer, buffer, salt, solvent, binder and / or preservative.

16. The composition according to claim 15, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

17. The composition according to claim 15 or 16, wherein the composition is a pharmaceutical composition.

18. A pharmaceutical composition comprising at least one cyclic peptide containing the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by Sequence ID No. 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, wherein the amino acid residues of the peptide are D-amino acid residues, and the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, excipient and / or additive.

19. The pharmaceutical composition according to claim 18, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

20. A pharmaceutical composition according to claim 18 or 19 for use in a method for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

21. A method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder, comprising the step of administering to a subject in need of such treatment an effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, or any functional derivative thereof, or any vehicle, matrix, nanoparticles or microparticles thereof, or any composition comprising the same, wherein the amino acid residues of the peptide are D-amino acid residues.

22. The method according to claim 21, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

23. The method according to claim 21 or 22, comprising administering a composition comprising at least one cyclic peptide as described in any one of claims 2 to 14.

24. The method according to any one of claims 21 to 23, further comprising administering at least one additional anticancer agent to the subject.

25. The method according to any one of claims 21 to 24, wherein the at least one cyclic peptide does not increase the level of bilirubin in the subject.

26. A method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder, comprising the step of administering a therapeutically effective amount of a cyclic peptide (the amino acid residues of the peptide being D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by Sequence ID No. 1, for use in a subject requiring such treatment, comprising a cyclic peptide, any functional derivative thereof, any vehicle, matrix, nanoparticles or microparticles thereof, or any composition containing the same.

27. The cyclic peptide for use according to claim 26, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

28. A cyclic peptide for use according to claim 26 or 27, comprising administering a composition comprising at least one cyclic peptide as described in any one of claims 2 to 14.

29. A cyclic peptide for use according to any one of claims 26 to 28, further comprising administering at least one additional anticancer agent to the subject.

30. The cyclic peptide for use according to any one of claims 26 to 29, wherein the at least one cyclic peptide does not increase the level of bilirubin in the subject.

31. A combination composition comprising at least one cyclic peptide containing the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown in Sequence ID No. 1, or any functional derivative thereof (the amino acid residues of the peptide are D-amino acid residues), and at least one anticancer agent or any pharmaceutically acceptable salt thereof.

32. The combination composition according to claim 31, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

33. The combination composition according to claim 31 or 32 for use in a method for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder.

34. A method for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder, comprising the step of administering to a subject in need thereof a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, or any functional derivative thereof (where the amino acid residues of the peptide are D-amino acid residues), at least one anticancer agent or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

35. The method according to claim 34, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

36. The method according to claim 34 or 35, wherein the at least one cyclic peptide does not increase the level of bilirubin in the subject.

37. (a) A compound comprising at least one cyclic peptide or any functional derivative thereof containing the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by Sequence ID No. 1, and at least one anticancer agent or a pharmaceutically acceptable salt thereof, wherein the amino acid residues of the peptide are D-amino acid residues or any pharmaceutically acceptable salt thereof, and optionally included in the first dosage form, (b) at least one anticancer agent, which is optionally included in the second dosage form, A kit that includes this.

38. The kit according to claim 37, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

39. The kit according to claim 37 or 38, for use in a method for treating, preventing, improving, reducing, or delaying the onset of at least one proliferative disorder in a subject requiring it.

40. A method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject exhibiting high bilirubin levels, comprising the step of administering to the subject a therapeutically effective amount of at least one cyclic peptide comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys represented by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

41. A method for treating, preventing, improving, reducing or delaying the onset of at least one proliferative disorder in a subject treated with at least one agent for treating high bilirubin levels, comprising the step of administering to the subject a therapeutically effective amount of at least one cyclic peptide (where the amino acid residues of the peptide are D-amino acid residues) comprising the amino acid sequence Trp-Trp-Thr-Phe-Phe-Leu-Pro-Ser-Thr-Leu-Trp-Glu-Arg-Lys shown by SEQ ID NO: 1, or any functional derivative thereof, or a pharmaceutically acceptable salt thereof, or any composition, kit, or combination thereof.

42. The method according to claim 40 or 41, wherein the at least one cyclic peptide is one of those described in any one of claims 2 to 14.

43. The method according to any one of claims 40 to 42, wherein the subject suffers from at least one disease and / or condition related to high bilirubin levels.

44. The method according to claim 43, wherein the at least one disease associated with the high bilirubin level is at least one of liver disease, blood disorders, biliary duct disorders and / or hereditary disorders.

45. The method according to any one of claims 40 to 44, wherein the high bilirubin level is caused by medication, infection and / or at least one physiological factor.

46. The method according to any one of claims 40 to 45, wherein at least one agent for treating the high bilirubin levels is at least one ursodeoxycholic acid (UDCA) or ursodiol, rifampicin, phenobarbital, cholestyramine and / or N-acetylcysteine ​​(NAC).

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