Tranexamic acid-class arginine and histidine mimetics as therapeutic agents

Abstract

In various embodiments, the disclosure relates to compositions and methods for the prevention or treatment of cancer, for the prevention, treatment or inhibition of viral or microbial infection or replication, or for the prevention, treatment or inhibition of other diseases. In some embodiments, the compositions include at least one of an arginine mimetic (TA-R) or a histidine mimetic (TA-H), or administration thereof. In some embodiments, at least one TA-R or TA-H is selected from the group consisting of trans-4-guanidinomethylcyclohexanecarboxylic acid (TA-R1), amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe), amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2), cis-amino(((3-carboxycyclohexyl) The TA-R may include, but is not limited to, cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3), cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4), compounds having cycloalkanes with two or more functional groups of cycloalkanes, derivatives thereof, salts thereof, and combinations thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to U.S. Provisional Patent Application No. 63 / 324,115, filed March 27, 2022, the disclosure of which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to therapeutic agents and more particularly, but not exclusively, to tranexamic class arginine and histidine mimetics as therapeutic agents. [Background technology]

[0003] This section provides background information to facilitate a better understanding of the various aspects of the present disclosure. It should be understood that the statements in this section of the document are to be read in this light, and not as admissions of prior art.

[0004] Tranexamic acid (TA) is a clinically used agent that prevents plasmin formation by occupying the lysine (Lys) binding site of plasminogen. TA is a synthetic analogue of Lys created by interposing a cyclohexyl ring between the carboxyl and amino side chains of Lys. Traditionally used as an antifibrinolytic agent, TA has recently been shown to suppress the viability of a broad set of human and mouse cancer cell lines and inhibit the replication of a number of viruses and microorganisms. Summary of the Invention

[0005] This Summary is provided to introduce a selection of concepts that are further described below in the Detailed Description. This Summary is not intended to identify key or essential features of the claimed subject matter, nor is it used as an aid in limiting the scope of the claimed subject matter.

[0006] In one embodiment, the present disclosure relates to a composition for preventing or treating cancer. In general, the composition comprises an arginine mimetic (TA-R), including trans-4-guanidinomethylcyclohexane carboxylic acid (TA-R1), amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe), amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R3), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R4), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R5), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R6), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R7), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R8), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R9), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R10), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R11), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R12), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R13), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R14), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R15), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R The functional groups may include, but are not limited to, cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3), cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4), compounds having a cycloalkane with two or more functional groups of the cycloalkane, derivatives thereof, salts thereof, and combinations thereof.

[0007] In some embodiments, the arginine mimetic has a concentration in the range of 0.5-20% (w / v). In some embodiments, the arginine mimetic preserves the spatial relationship between the carboxyl group and the guanidinium group of the amino acid. In some embodiments, the arginine mimetic inhibits cell viability. In some embodiments, the cell comprises a cancer cell. In some embodiments, the cancer cell is a breast cancer cell. In some embodiments, the arginine mimetic reduces expression of the MYC oncogene. In some embodiments, the arginine mimetic reduces histone acetylation. In some embodiments, the arginine mimetic inhibits p300 acetyltransferase activity. In some embodiments, the arginine mimetic reduces programmed death-ligand 1 (PD-L1) expression in the cancer cell, thereby blocking T cell-based immunity.

[0008] In a further embodiment, the present disclosure relates to a method for preventing or treating cancer. In general, the method comprises administering an arginine mimetic (TA-R) to a subject. In some embodiments, TA-R can include, without limitation, trans-4-guanidinomethylcyclohexanecarboxylic acid (TA-R1), amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe), amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2), cis-amino(((3-carboxycyclohexyl)methyl)amino)methaniminium chloride (TA-R3), cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4), compounds having cycloalkanes with two or more functional groups of cycloalkanes, derivatives thereof, salts thereof, and combinations thereof.

[0009] In some embodiments, the arginine mimetic has a concentration in the range of 0.5-20% (w / v). In some embodiments, the method further comprises preserving the spatial relationship between the carboxyl group and the guanidinium group of the amino acid by the arginine mimetic. In some embodiments, the method further comprises inhibiting cell viability by the arginine mimetic. In some embodiments, the cell includes a cancer cell. In some embodiments, the cancer cell is a breast cancer cell. In some embodiments, the method further comprises reducing expression of the MYC oncogene by the arginine mimetic. In some embodiments, the method further comprises decreasing histone acetylation by the arginine mimetic. In some embodiments, the method further comprises inhibiting p300 acetyltransferase activity by the arginine mimetic. In some embodiments, the method further comprises reducing programmed death-ligand 1 (PD-L1) expression in the cancer cell and blocking T cell-based immunity by the arginine mimetic.

[0010] In additional embodiments, the present disclosure relates to compositions for the prevention or treatment of cancer, for the prevention, treatment or inhibition of viral or microbial infection or replication, or for the prevention, treatment or inhibition of disease. Generally, the compositions include at least one of an arginine mimetic (TA-R) or a histidine mimetic (TA-H).

[0011] In some embodiments, at least one of TA-R or TA-H is selected from the group consisting of trans-4-guanidinomethylcyclohexanecarboxylic acid (TA-R1), amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe), amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2), cis-amino(((3-carboxycyclohexyl )methyl)amino)methaniminium chloride (TA-R3), cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4), compounds having a cycloalkane with two or more functional groups of the cycloalkane, derivatives thereof, salts thereof, and combinations thereof. In some embodiments, at least one of the TA-R or TA-H has a concentration in the range of 0.5-20% (w / v). In some embodiments, at least one of the TA-R or TA-H preserves the spatial relationship between the carboxyl group of the amino acid and the guanidinium group. In some embodiments, at least one of the TA-R or TA-H treats or prevents the progression or proliferation of cancer, a viral or microbial infection, or the progression of another disease. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is breast cancer. In some embodiments, at least one of the TA-R or TA-H reduces expression of the MYC oncogene. In some embodiments, at least one of the TA-R or TA-H reduces histone acetylation. In some embodiments, at least one of the TA-R or TA-H inhibits p300 acetyltransferase activity. In some embodiments, at least one of the TA-R or TA-H reduces programmed death-ligand 1 (PD-L1) expression in cancer cells, thereby blocking T cell-based immunity.

[0012] In further embodiments, the present disclosure relates to a method for preventing or treating cancer, for preventing, treating or inhibiting viral or microbial infection or replication, or for preventing, treating or inhibiting disease.Generally, the method comprises administering at least one of arginine mimetic (TA-R) or histidine mimetic (TA-H) to a subject.

[0013] In some embodiments, at least one of TA-R or TA-H is selected from the group consisting of trans-4-guanidinomethylcyclohexanecarboxylic acid (TA-R1), amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe), amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R3), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R4), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R5), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R6), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R7), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R8), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R9), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R10), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R11), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R12), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R13), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R14), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R15), cis-amino(((3-carboxycyclohexyl)amino)methaniminium chloride (TA-R16), cis-amino(((3-carboxycyclo The TA-R includes, without limitation, cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3), cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4), compounds having a cycloalkane with two or more functional groups of the cycloalkane, derivatives thereof, salts thereof, and combinations thereof. In some embodiments, at least one of the TA-R or TA-H has a concentration in the range of 0.5-20% (w / v). In some embodiments, the method further comprises preserving the spatial relationship of the carboxyl group of the amino acid and the guanidinium group by at least one of the TA-R or TA-H. In some embodiments, the method further comprises treating or preventing the progression or proliferation of cancer, viral or microbial infection, or progression of another disease by at least one of the TA-R or TA-H. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the method further comprises reducing expression of MYC oncogene by at least one of TA-R or TA-H. In some embodiments, the method further comprises decreasing histone acetylation by at least one of TA-R or TA-H. In some embodiments, the method further comprises inhibiting p300 acetyltransferase activity by at least one of TA-R or TA-H.In some embodiments, the method further includes reducing programmed death-ligand 1 (PD-L1) expression in cancer cells by at least one of TA-R or TA-H, and blocking T cell-based immunity.

[0014] A more complete understanding of the subject matter of the present disclosure can be obtained by reference to the following detailed description when taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0015] [Figure 1] Illustrates arginine mimetics induced by tranexamic acid (TA) (TA-R). [Diagram 2] The TA-R compounds are illustrated to reduce breast cancer cells (MDA-MB-468) to a greater extent than tranexamic acid (TA); the cis-amino(((3-carboxycyclohexyl)methyl)amino)methaniminium chloride (TA-R3) curve is truncated due to insolubility. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] It will be understood that the following disclosure presents many different embodiments or examples to incorporate different features of various embodiments.To simplify the disclosure, specific examples and arrangements of components are described below.These are, of course, merely examples and are not intended to be limiting.The headings of the chapters used herein are for organizational purposes and are not to be construed as limiting the subject matter described.

[0017] As used herein, the term "tranexamic acid" (a class, type, or mimetic of a compound) refers to a compound having a cycloalkane with two or more functional groups of the cycloalkane. For example, in the case of tranexamic acid, a "lysine mimetic," the cycloalkane has two functional groups: (1) C 4 (2) an aminomethyl group on atom C; and 1In the case of "arginine mimetics," the cycloalkane can be a cyclohexane having two functional groups: (1) a carboxylic acid group on the C atom, and thus an amine group similar to that of lysine. 4 guanidinomethyl group on atom; and (2) C 1 The functional group can be cyclohexane, having a carboxylic acid group on the atom, thus having a guanidinium group similar to that of arginine. It should be noted that the foregoing are only examples, and various configurations are readily envisioned. For example, the cycloalkane can be cyclopentane, and the functional group can be C 4 Atoms and C 1 It is not necessary that the functional group be on an atom. In addition, the functional group is not limited to a carboxyl group, but may include a variety of functional groups, such as an ester group, for example. Further examples include, without limitation, the following: trans-4-guanidinomethylcyclohexanecarboxylic acid; Amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride; Amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride; cis-amino(((3-carboxycyclohexyl)methyl)amino)methaniminium chloride; cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride; and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid.

[0018] Traditionally used as an antifibrinolytic drug, tranexamic acid (TA) has recently been shown to suppress the viability of a broad set of human and mouse cancer cell lines and inhibit the replication of numerous viruses and microorganisms. There are plasmin-dependent and plasmin-independent biochemical mechanisms governing this response, including inhibition of protein synthesis and suppression of lysine (Lys) acetylation. More specifically, it has also been recently shown that the basic mode of action (MOA) of TA is that it mimics (antagonizes) not only Lys but also arginine (Arg) and histidine (His), three positively charged amino acids essential for electrostatic binding required in multiple protein-protein interactions, and other processes involved in cancer formation, viral and microbial replication, and the progression of other diseases and conditions.

[0019] In addition to blocking Lys binding sites on plasminogen to inhibit the formation of plasmin, specific examples of this fundamental MOA that have been demonstrated include, for example, inhibition of Lys acetylation (required for the generation of proteins involved in viral replication and progression of cancer and other diseases) and occupancy of cationic amino acid transporters (CATs) required by Lys, Arg and His to be transported into cells, thereby depriving cells of these amino acids and inhibiting the generation of proteins required for viral replication and cancer growth.

[0020] Based on the hypothesis that synthetic "tranexamic" mimetics of Arg or synthetic "tranexamic" mimetics of His may be more effective than TA against certain cancers, viruses, or other diseases or conditions (whether or not because Arg or His play a more important role in these cases or for other reasons), the present disclosure relates to the creation of a variety of synthetic "tranexamic" mimetics of Arg that were tested against common breast cancer lines. The present disclosure shows that all of the Arg mimetics were indeed significantly more effective than TA in suppressing the viability of this type of cancer. As such, the present disclosure opens the possibility of using synthetic "tranexamic" mimetics of Arg and "tranexamic" mimetics of His against viruses, microorganisms, cancers, and other diseases or conditions when TA does not provide inhibition or sufficient inhibition, as well as using them in combination with TA or in combination with other agents to confer increased efficacy or safety.

[0021] Reported herein are the results of the development of several TA-R molecules, including biological testing as examples. The following summarizes the various TA-R abbreviations used herein: trans-4-guanidinomethylcyclohexanecarboxylic acid (TA-R1); amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe); amino(((1r,4r)-4-carboxycyclohexyl)amino)methaniminium chloride (TA-R2); cis-amino(((3-carboxycyclohexyl)methyl)amino)methaniminium chloride (TA-R3); cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe); and cis-3-(guanidinomethyl)cyclopentane-1-carboxylic acid (TA-R4).

[0022] Design and preparation of arginine mimetics As a first overview, TA mimics Lys by preserving the 1,6-connectivity between the carboxyl functionality and the amino group present on the Lys side chain. It is known that the trans stereochemistry of TA and the cyclohexyl ring is important for plasminogen binding, the former preserving the extended conformation of the molecule, and the latter conferring stabilization of van der Waals contacts within the Lys binding site. By analogy, several Arg mimetics have been defined and studied for biological evaluation that preserve the spatial relationship (e.g., 1,5-connectivity) between the carboxyl group of the amino acid and the guanidinium group (TA-R1 and TA-R1OMe being the exceptions). These molecular targets are defined in Figure 1, with the designation TA-R, and complemented by a variety of key descriptors. Also shown are comparator compounds, TA and TA-NAc (N-acetylcysteine; NAc), that have been evaluated in parallel. EXAMPLES

[0023] Reference will now be made to more specific embodiments of the present disclosure and data supporting such embodiments. It should be noted, however, that the following disclosure is for illustrative purposes only and is not intended to limit the scope of the claimed subject matter in any way.

[0024] Biological testing Effect of compounds on cell viability MDA-MB468 triple-negative breast cancer cells were seeded at 6,250 cells per well in 96-well plates and incubated overnight at 37° C. Cells were subsequently incubated for 72 h at 37° C. with increasing concentrations of each TA analogue shown in FIG. 1. Cell viability was assessed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay performed according to the manufacturer's instructions.

[0025] Inhibition of p300 acetyltransferase activity p300 enzyme assays were performed with TA, TA-NAc and TA-R2, using commercially available recombinant p300, and recombinant commercially available histone H3, and tritiated acetyl-CoA as substrate. P300 assays were performed in the presence of increasing concentrations of each compound, and p300 acetylation was assessed by scintillation counting of histone H3 adsorbed to nitrocellulose squares after extensive washing of the 1 cm x 1 cm nitrocellulose squares with 20% trichloroacetic acid.

[0026] Results and Discussion Chemical synthesis and solubility TA was purchased from a commercial source and TA-NAc was prepared directly through acetylation of TA based on standard practice. TA-NAc was isolated and tested as its sodium salt, which exhibits better water solubility.

[0027] TA-R1-R4 were accessible from their corresponding amino acids through treatment with methylisothiourea hemisulfate. TA-R1 (trans-4-guanidinomethylcyclohexanecarboxylic acid; GMCHA) was prepared in one step from TA using this reagent, but exhibited poor water solubility in its neutralized form and as its salt. Esterification of TA-R1 to generate the new compound TA-R1OMe improved the solubility for the preparation of a 2% (w / v) solution in phosphate buffered saline (PBS) buffer (pH=7.4) and in biological testing. TA-R2 was prepared in one step from commercially available trans-4-aminocyclohexanecarboxylic acid and exhibited good water solubility.

[0028] The essential amino acids for the synthesis of TA-R3 / R4 required a multi-step synthetic approach. Briefly, the preparation of the new compound TA-R3 proceeded through eight consecutive synthetic steps, starting from cis-1,3-cyclohexanedicarboxylic acid, to give the product as its HCl salt. Protection / deprotection of the amino groups was required to facilitate purification, which was a sequence of stepwise oxidation of the alcohol to the carboxylic acid. The compound exhibited poor aqueous solubility (about 0.1% in PBS buffer), which was remedied by esterification to produce TA-R3OMe (to prepare a about 2% solution). The approach to the known compound TA-R4 required one additional step to generate the starting dicarboxylic acid, in this case through oxidative cleavage of norbornene. TA-R4 demonstrated sufficient solubility in this neutralized form (about 2% solution in PBS buffer). All final compounds were 1 H nuclear magnetic resonance (NMR), 13 It was fully characterized by 1 C NMR and high-resolution electrospray ionization mass spectrometry (HRMS-ESI).

[0029] biological results TA-R compounds suppress cancer cell viability in vitro MTT cell viability assays showed that the tested TA-R compounds suppressed breast cancer (MDA-MB-468) cell viability (Figure 2) to a greater extent than TA (or TA-NAc; data not shown).

[0030] Biochemical evaluation of treatment of breast cancer cells with TA-R2 Immunoblot analysis of treatment of MDA-MB-468 cells with TA-R2 versus TA and TA-NAc (NAc-TA) showed that TA-R2 reduced expression of the MYC oncogene to a greater extent than TA or NAc-TA at the same concentration. High (2%) TA-R2 reduced programmed death-ligand 1 (PD-L1), whereas the other two compounds did not. This is important because PD-L1 expression on cancer cells blocks T cell-based immunity. Therefore, TA-R2 would be predicted to raise anti-cancer immunity in immune-preserving systems. A histone acetyltransferase (HAT) enzyme assay was used to determine whether TA-R2 inhibited p300 activity. While TA (2%) did not affect p300 acetylation of Histon 3 (H3) in vitro, TA-R2 reduced histone acetylation more potently than the other two compounds. This is consistent with the hypothesis that TA acts in part by inhibiting acetyltransferases such as p300 / CPB that acetylate histones, which in controls is not observed in the absence of H3 / p300 or acetyl-coenzyme A (Acetyl CoA).

[0031] conclusion All of the TA-R analogs tested had IC values ​​approximately 10-fold lower for TA-R1-OMe, TA-R3, and TA-R3-OMe. 50The analogs exhibit higher cytotoxic potency against the MDA-MB-468 triple-negative breast cancer cell line than TA, with a β-aminobutyric acid (NA) value. Difficulties associated with the low solubility of some analogs were addressed by producing ester derivatives in some cases and by forming the compounds as salts in others (or both). One of the analogs tested, TA-R2, downregulated expression of the MYC oncogene and reduced histone acetylation to a greater extent than TA at 2% (w / v) concentration, and unlike TA, TA-R2 downregulated MYC at 0.5%. Overall, these results indicate that replacing the amine groups of TA or TA-evoked compounds with guanidinium groups can enhance anticancer potency and activity through biochemical mechanisms that overlap with those of TA.

[0032] Based on the results presented above, it is clear that although TA has been shown to antagonize Lys, Arg, and His, Arg mimetics, such as the TA-R molecule discussed above, are more effective than TA in certain situations. It is readily envisioned that additional situations exist. For example, Arg deficiency has been identified as a treatment method for additional types of cancers and for the virus that caused the coronavirus disease 2019 (COVID-19) pandemic (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2). If TA-R is more effective than TA in antagonizing Arg, as is often the case, then it will be more effective in these additional therapeutic areas.

[0033] In addition, based on the data presented herein, it is further envisioned that the use of the TA-R mimetics discussed herein may provide a means to improve the efficacy of radiation treatment for certain tumor types, such as glioblastoma, since Arg deficiency has been shown to improve the efficacy of radiation treatment for these tumors.Furthermore, since Arg is also involved in aspects of the physiological response to traumatic brain injury, the mimetics disclosed herein may be utilized in the treatment of brain injuries, including, for example, concussion.

[0034] While various embodiments of the present disclosure have been illustrated in the accompanying drawings and described in the foregoing Detailed Description, it will be understood that the present disclosure is not limited to the embodiments disclosed herein, but is capable of numerous rearrangements, modifications, and substitutions without departing from the spirit of the present disclosure as set forth herein.

[0035] The term "substantially" is defined as most, but not necessarily all, of what is specified, as understood by one of ordinary skill in the art. In any disclosed embodiment, the terms "substantially," "approximately," "generally," and "about" can be substituted for "within [a percentage]" of what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.

[0036] The foregoing summarizes features of some embodiments so that those skilled in the art may better understand the aspects of the present disclosure. Those skilled in the art should recognize that they can readily use the present disclosure as a basis for designing or modifying other processes and structures to carry out the same purposes and / or achieve the same advantages of the embodiments introduced herein. Those skilled in the art should also recognize that such equivalent structures do not depart from the spirit and scope of the present disclosure, and that they can make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure. The scope of the present invention should be determined solely by the language of the claims that follow. The term "comprising" in the claims is intended to mean "including at least" such that the recited enumeration of elements in the claims is an open group. The terms "a," "an," and other singular terms are intended to include the plural forms thereof unless specifically excluded.

Claims

1. A composition for the prevention or treatment of cancer, Arginine mimetic (TA-R) selected from the group consisting of amino((((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R1-OMe) or cis-amino(((3(methoxycarbonyl)cyclohexyl)methyl)amino)methaniminium chloride (TA-R3-OMe), and combinations thereof. A composition containing the following:

2. The composition according to claim 1, wherein the arginine mimetic is present in a concentration within the range of 0.5 to 20% (w / v).

3. The composition according to claim 1, wherein the arginine mimetic maintains the spatial relationship between the carboxyl group and the guanidinium group of the amino acid.

4. The composition according to claim 1, wherein the arginine mimetic inhibits the viability of cells.

5. The composition according to claim 4, wherein the cells include cancer cells.

6. The composition according to claim 5, wherein the cancer cells are breast cancer or skin cancer cells.

7. The composition according to claim 1, wherein the arginine mimetic reduces the expression of the MYC oncogene.

8. The composition according to claim 1, wherein the arginine mimetic reduces histone acetylation.

9. The composition according to claim 1, wherein the arginine mimetic inhibits p300 acetyltransferase activity.

10. The composition according to claim 1, wherein the arginine mimetic reduces the expression of programmed death ligand 1 (PD-L1) in cancer cells, thereby blocking T cell-based immunity.

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