Compositions, methods and uses of cape derivatives for treating human diseases characterized by HDAC1 dysregulation

Abstract

Methods, uses and compositions for inhibiting the proliferation or growth of or eliminating one or more cells that express HDAC1 including contacting the one or more cells with an effective amount of a CAPE derivative selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester / (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester / (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester / (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate.

Description

COMPOSITIONS, METHODS AND USES OF CAPE DERIVATIVES FOR TREATING HUMAN DISEASES CHARACTERIZED BY HDAC1 DYSREGULATIONFIELD

[0001] The present disclosure relates to the field of treatment of human diseases characterized by HDAC1 dysregulation.BACKGROUND

[0002] HDAC1 (Histone deacetylase 1) is an enzyme that plays a role in regulating gene expression by removing acetyl groups from histone proteins, which can result in the tightening of chromatin structure and repression of gene transcription.

[0003] HDAC1 inhibitors have shown promise as anticancer agents. By inhibiting HDAC1 activity, these small molecules (HDACi) can promote the acetylation of histones, leading to a more open chromatin structure. This allows for the expression of tumor suppressor genes and inhibits the expression of oncogenes, ultimately suppressing cancer cell growth and promoting cell death.

[0004] Aberrant activity and / or overproduction of HDAC1 has been implicated in various human diseases, including cancer, neurodegenerative disorders, and inflammatory conditions.

[0005] Better treatments for human diseases characterized by HDAC1 dysregulation would be desirable.SUMMARY OF THE INVENTION

[0006] The present invention relates at least in part to binding, interacting with or altering HDAC1 activity using certain Caffeic Acid Phenethyl Ester (CAPE) derivatives.

[0007] In one aspect, the present invention provides a method for inhibiting the proliferation or growth of or eliminating one or more cells that express HDAC1 including contacting the one or more cells with an effective amount of a CAPE derivative selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3- (3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3- phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester / (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate.

[0008] In one aspect, the present invention provides a selective method for inhibiting the proliferation or growth of or eliminating one or more cells that express HDAC1 including contacting the one or more cells with an effective amount of a CAPE derivative selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2- phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate. In another aspect, the CAPE derivative is at a concentration of 1 pM to 10 pM. In a further aspect, the CAPE derivative is at a concentration of 5pM to 10 pM. In a still further aspect, the CAPE derivative is at a concentration of 2.5pM to 5 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM. In another aspect, the cells express HDAC1 dysregulation and the method selectively binds, interacts with or alters the HDAC1 activity of the cells.

[0009] In another aspect, the present invention provides a method for treating a tumor comprising cells that express HDAC1 , the method including administering to an individual in need of treatment for the tumor an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester / (E)- 3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester / (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM.

[0001] In another aspect, the present invention provides a selective method fortreating a tumor comprising cells that express HDAC1 , the method including administering to an individual in need of treatment for the tumor an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester / (E)- 3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester / (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM. In another aspect, the cells express HDAC1 dysregulation and the method selectively binds, interacts with or alters the HDAC1 activity of the cells.

[0002] In another aspect, the present invention provides a method for treating a disease condition that expresses HDAC1 , the method including administering to an individual in need of treatment forthe disease condition an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2- phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM. In certain aspects, the disease condition is selected from the group consisting of temozolomide resistant glioma, hormone refractory prostate cancer, acute myeloid leukemia, peripheral t-cell lymphoma (particularly the alk-ve anaplastic large-cell lymphoma), extranodal nk / t-cell lymphoma, neurodegenerative disorders (with HDAC1 overexpression or high activity) such as the amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, reduction of proinflammatory cytokines in inflammatory bowel disease (IBD), reduction of proinflammatory cytokines in asthma, suppression of proinflammatory cytokines in rheumatoid arthritis, and reduction of proinflammatory cytokines in allergic rhinitis and atopic dermatitis.

[0003] In another aspect, the present invention provides a selective method for treating a disease condition that expresses HDAC1 , the method including administering to an individual in need of treatment for the disease condition an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5 pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM. In another aspect, the cells express HDAC1 dysregulation and the method selectively binds, interacts with or alters the HDAC1 activity of the cells. In certain aspects, the disease condition is selected from the group consisting of temozolomide resistant glioma, hormone refractory prostate cancer, acute myeloid leukemia, peripheral t-cell lymphoma (particularly the alk-ve anaplastic large-cell lymphoma), extranodal nk / t-cell lymphoma, neurodegenerative disorders (with HDAC1 overexpression or high activity) such as the amyotrophic lateralsclerosis (ALS) and Parkinson’s disease, reduction of proinflammatory cytokines in inflammatory bowel disease (IBD), reduction of proinflammatory cytokines in asthma, suppression of proinflammatory cytokines in rheumatoid arthritis, and reduction of proinflammatory cytokines in allergic rhinitis and atopic dermatitis.

[0004] In another aspect, the present invention provides use of an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate for treating a disease condition that expresses HDAC1 dysregulation. In certain embodiments, the disease condition is selected from the group consisting of temozolomide resistant glioma, hormone refractory prostate cancer, acute myeloid leukemia, peripheral t-cell lymphoma (particularly the alk-ve anaplastic large-cell lymphoma), extranodal nk / t-cell lymphoma, neurodegenerative disorders (with HDAC1 overexpression or high activity) such as the amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, reduction of proinflammatory cytokines in inflammatory bowel disease (IBD), reduction of proinflammatory cytokines in asthma, suppression of proinflammatory cytokines in rheumatoid arthritis, and reduction of proinflammatory cytokines in allergic rhinitis and atopic dermatitis. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5 pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM.

[0005] In another aspect, the present invention provides use of an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate for selectively treating a disease condition that expresses HDAC1 dysregulation. In certain embodiments, the disease condition is selected from the group consisting of temozolomide resistant glioma, hormone refractory prostate cancer, acute myeloid leukemia, peripheral t-cell lymphoma (particularly the alk-ve anaplastic large-cell lymphoma), extranodal nk / t-cell lymphoma, neurodegenerative disorders (with HDAC1 overexpression or high activity) such as the amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, reduction of proinflammatory cytokines in inflammatory bowel disease (IBD), reduction of proinflammatory cytokines in asthma, suppression of proinflammatory cytokines in rheumatoid arthritis, and reduction ofproinflammatory cytokines in allergic rhinitis and atopic dermatitis. In another aspect, the use of the agent is for selective inhibition of the level and / or activity of HDAC1 in a cell. In another aspect, the agent is at a concentration of 1 pM to 10 pM. In a further aspect, the agent is at a concentration of 5 pM to 10 pM. In a still further aspect, the agent is at a concentration of 2.5 pM to 5 pM.

[0010] In another aspect, the present invention provides a selective pharmaceutical composition including an effective amount of a CAPE derivative selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3- phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate, and a pharmaceutically acceptable carrier. In another aspect, the CAPE derivative is at a concentration of 1 pM to 10 pM. In a further aspect, the CAPE derivative is at a concentration of 5 pM to 10 pM. In a still further aspect, the CAPE derivative is at a concentration of 2.5 pM to 5 pM. In another aspect, one or more CAPE derivatives are selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate. In another aspect, the cells express HDAC1 dysregulation and the method selectively binds, interacts with or alters the HDAC1 activity of the cells.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] For the purpose of illustrating the invention, the drawings show aspects of one or more embodiments of the invention. However, it should be understood that the present invention is not limited to the precise arrangements and instrumentalities shown in the drawings, wherein:

[0007] FIG. 1 is a table of structures of certain HDAC inhibitors, CAPE and CAPE derivatives;

[0008] FIG. 2 is a table of docking results of testing certain HDAC inhibitors, CAPE and CAPE derivatives;

[0009] FIG. 3 are images showing molecular docking of certain commercial compounds tested;

[0010] FIG. 4 are images showing molecular docking of certain compounds tested including CAPE-D1 and CAPE-D2;

[0011] FIG. 5 is an image showing molecular docking of tested compound CAPE-D3;

[0012] FIG. 6 is a graph of growth inhibition of a human non-Hodgkin lymphoma cell line for various test compounds; and,

[0013] FIG. 7 is a graph of growth inhibition of a human non-Hodgkin lymphoma cell line for CAPE-D3.DETAILED DESCRIPTIONDefinitions

[0014] An “effective amount” or “effective dose” of a compound or other agent (or composition containing such compound or agent) refers to the amount sufficient to achieve a desired biological and / or pharmacological effect, e.g., when delivered to a cell or organism according to a selected administration form, route, and / or schedule. As will be appreciated by those of ordinary skill in this art, the absolute amount of a particular compound, agent, or composition that is effective may vary depending on such factors as the desired biological or pharmacological endpoint, the agent to be delivered, the target tissue, etc. Those of ordinary skill in the art will further understand that an “effective amount” may be contacted with cells or administered in a single dose, or the desired effect may be achieved by use of multiple doses. An effective amount of a composition may be an amount sufficient to reduce the severity of or prevent one or more symptoms or signs of a disorder.

[0015] “Contacting”, “contacting the cell” and any derivations thereof as used herein, refers to any means of introducing an agent (e.g., nucleic acids, oligopeptides, ribozymes, antibodies, small molecules, etc.) into a target cell, including chemical and physical means, whether directly or indirectly or whether the agent physically contacts the cell directly or is introduced into an environment in which the cell is present. Contacting also is intended to encompass methods of exposing a cell, delivering to a cell, or ‘loading’ a cell with an agent by viral or non-viral vectors, and wherein such agent is bioactive upon delivery. The method of delivery will be chosen for the particular agent and use (e.g.,cancer being treated). Parameters that affect delivery, as is known in the medical art, can include, inter alia, the cell type affected (e.g., tumor), and cellular location. In some embodiments, contacting includes administering the agent to a subject. In some embodiments, contacting refers to exposing a cell or an environment in which the cell is located to one or more HDAC inhibitors of the present invention.

[0016] "HDAC1 dysregulation" in one aspect of the present invention refers to HDAC1 activity or function or level in a target cell being affected; in another aspect to overproduction of HDAC1 ; and in a further aspect, to a change in HDAC1 level; in another aspect, to a change in HDAC1 function, and in a still further aspect, high HDAC1 activity, all of the foregoing relative to HDAC1 status in a normal healthy target cell.

[0017] “Treat”, “treating” and similar terms refer to providing medical and / or surgical management of a subject. Treatment can include, but is not limited to, administering a compound or composition (e.g., a pharmaceutical composition or a composition comprising appropriate cells in the case of cell-based therapy) to a subject. Treatment is typically undertaken in an effort to alter the course of a disorder (which term is used to refer to a disease, syndrome, or abnormal condition) or undesirable or harmful condition in a manner beneficial to the subject. The effect of treatment can generally include reversing, alleviating, reducing severity of, delaying the onset of, curing, inhibiting the progression of, and / or reducing the likelihood of occurrence or reoccurrence of the disorder or condition, or one or more symptoms or manifestations of such disorder or condition. A composition can be administered to a subject who has developed a disorder or is at risk of developing a disorder. A composition can be administered prophylactically, i.e., before development of any symptom or manifestation of a disorder. Typically, in this case the subject will be at increased risk of developing the disorder relative to a member of the general population. For example, a composition can be administered to a subject with a risk factor, e.g., a mutation in a gene, wherein the risk factor is associated with increased likelihood of developing the disorder but before the subject has developed symptoms or manifestations of the disorder. “Preventing” can refer to administering a composition to a subject who has not developed a disorder, so as to reduce the likelihood that the disorder will occur or so as to reduce the severity of the disorder should it occur. The subject may be identified (e.g., diagnosed by a medical practitioner) as having or being at risk of developing the disorder (e.g., at increased risk relative to many most other members of the population or as having a risk factor that increases likelihood of developing the disorder).

[0018] Pharmaceutical compositions for use in the present invention can include compositions comprising one or a combination of HDAC1 inhibitors in an effective amount to achieve the intended purpose. The determination of an effective dose of a pharmaceutical composition of the invention is well within the capability of those skilled in the art. A therapeutically effective dose refers to that amount of active ingredient which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example the ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).

[0019] As used herein “activity” refers to a measure for the ability of a transcription product or a translation product to produce a biological effect or a measure for a level of biologically active molecules.Methods

[0020] The structural similarity of Caffeic Acid Phenethyl Ester (CAPE) with HDACi (hydroxamic acid class of HDAC inhibitors) and HDAC1 protein overexpression in several diseases prompted the present inventor to examine if certain CAPE derivatives (see Table 1 : CAPE-D1 , CAPE-D2 and CAPE-D3) can bind to HDAC1 by employing a blind molecular docking approach. In the present disclosure, the molecules in Table 1 are sometimes referred to by the short-hand CAPE-D1 , CAPE-D2 and CAPE-D3, and sometimes by both the chemical name and the IUPAC nomenclature for the particular molecule, with the chemical name and the IUPAC nomenclature separated by a forward slash. The molecules of Table 1 can also be referred to by only one of the molecule's chemical name, chemical structure and IUPAC nomenclature. The various means of referencing the molecules of Table 1 should be considered to be equivalent forms of reference for the three molecules disclosed Table 1 .Table 1Example Method

[0021] Molecules (Standard HDACi and CAPE derivatives) were docked with HDAC1 protein (Protein Data Bank ID: 4BKX) using AutoDock. Clustering of the docked conformation identified conformations with similar binding energy and pose on the protein. Representative docked conformation of the largest cluster was analyzed by LIGPLOT, a 2D ligand-protein interaction plot.

[0022] The molecules were downloaded from PubChem (Kim et al., 2021) in SMILES format and for those without known PubChem id, ChemDraw was used to draw and obtain the SMILES format of the molecule. Using CORINA 3D (Sadowski et al., 1994), the 1 D SMILES information was converted to a 3D structure and downloaded in the PDB format. Subsequently, all the structures were converted to the PDBQT format using OpenBabel (O'Boyle et al., 2011) after adding partial charges and hydrogens.

[0023] For the protein structure, HDAC1 structure was extracted from the Protein Data Bank (PDB id: 4BKX), to which hydrogens and partial charges were added using AutoDockTools and saved in the PDBQT format. Prior to this, crystallographic water was removed. The Zn2+ atom was defined in the docking parameter file to consider its contribution to substrate binding.

[0024] A blind docking approach was employed for identifying regions in the protein that are highly likely to be favorable for small molecule binding. Specifically, a grid box consisting of 126x126x126 points with a spacing of 0.38 A was constructed so that 90% of the protein is enclosed within the grid box. This enables that the molecule could possibly bind to a region that it finds favorable.

[0025] Each molecule was then docked with a detailed or an exhaustive setting using Lamarckian genetic algorithm with 100 dockings, each. Following which, clustering of the docked conformations was performed to identify conformations that have similar binding energy and spatial location on the protein. This is because the clustering of the low- energy conformations of a molecule with a high affinity would present a large cluster of similar conformations in a specific spatial location of the protein. The higher the number of conformations in a cluster would indicate a higher preference to bind to a specific region of the protein.

[0026] Each molecule was docked with the following parameters for detailed docking. Specifically, the number of individuals in the population was set to 150; maximum number of energy evaluations was set to 25000000, with maximum number of generations 27000, along with the rate of gene mutation as 0.02, and rate of crossover as 0.8. After the 100 rounds of docking the conformations were clustered and the cluster with maximum number of members for mapping their interactions was observed.

[0027] The coordinates of the representative docked conformation of the largest cluster were analyzed further by preparing a protein-ligand complex for generating a 2D interaction plot using LIGPLOT (Laskowski et al. ,2011) The list of protein residues making hydrogen bonds and non-specific hydrophobic interactions were analyzed further.Results

[0028] Molecular docking results demonstrate that HDACi, Entinostat and Panobinostat are better binders in terms of binding energy and interactions with crucial active site residues. The lead CAPE derivatives namely 2,5-dihydroxycinnamic acid 3-phenylpropyl ester / (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate were found to be better binders than CAPE [(3, 4- dihydroxy cinnamic acid) phenethyl ester] showing a similar binding pattern as HDACi, including zinc binding. The docking results are summarized in the table of FIG. 2.

[0029] In one embodiment, surprisingly, through molecular docking studies, three derivatives of CAPE were identified which have better HDAC1 binding than CAPE (See CAPE-D1 , CAPE-D2 and CAPE-D3 in the tables of FIG. 1 and FIG. 2). The better HDAC1 binding of the CAPE derivatives can be applied to selectively treat several diseases (with HDAC1 over-expression and / or high activity relative to a normal healthy cell) that have become resistant to standard chemotherapies. Diseases with HDAC1 over-expression and / or high activity relative to a normal healthy cell which can be selectively treated include the following:

[0030] Temozolomide Resistant Glioma

[0031] Hormone Refractory Prostate Cancer

[0032] Acute Myeloid Leukemia

[0033] Peripheral T-cell Lymphoma (particularly the ALK-ve anaplastic large-cell lymphoma)

[0034] Extranodal NK / T-cell lymphoma

[0035] Neurodegenerative disorders (with HDAC1 overexpression or high activity) such as the Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease

[0036] Reduction of proinflammatory cytokines in inflammatory bowel disease (IBD)

[0037] Reduction of proinflammatory cytokines in Asthma

[0038] Suppression of proinflammatory cytokines in Rheumatoid Arthritis

[0039] Reduction of proinflammatory cytokines in Allergic Rhinitis and Atopic DermatitisOverall Results

[0040] In FIG. 3, molecular docking of the commercial HDAC1 inhibitors SAHA, Panobinostat, Entinostat and Ricolinostat is depicted. Molecular docking of CAPE-D1 is depicted in the lower left quadrant of FIG. 4 and molecular docking of CAPE-D2 is depicted in the lower right quadrant of FIG. 4. In FIG. 4, a zinc ion (Zn2+) is indicated with reference numeral 2, a small molecule (being CAPE-D1 and CAPE-D2 as the case may be) is representedby reference numeral 6 and the structure of HDAC1 is generally indicated by reference numeral 4. In FIG. 4 and FIG. 5, key amino acid residues in HDAC1 protein making hydrogen bonds with CAPE or the CAPE derivatives CAPE-D1 , CAPE-D2 and CAPE- 03 are depicted with the three letter codes corresponding to each amino acid residue.

[0041] In FIG.5, molecular docking of CAPE-D3 is depicted. In FIG. 5, a zinc ion (Zn2+) is indicated with reference numeral 2, a small molecule (being CAPE-D3) is represented by reference numeral 6 and the structure of HDAC1 is generally indicated by reference numeral 4. Key amino acid residues are indicated in FIG. 5.

[0042] The molecular docking and subsequent protein-drug interaction data reveal that the widely used / standard HDACi such as TSA, SAHA, Entinostat, and Ricolinostat are good binders of HDAC1. All HDACi were observed to bind to Zn2+present in the catalytic domain of HDAC1 protein.

[0043] The analysis was done keeping the TSA as the standard HDACi, and it was observed that Panobinostat exhibited a better binding with large number of conformations in the highest ranked cluster (55 out of 100), relatively lower binding energy (-10.52 Kcal / mol) and interacts via hydrogen bonds with two residues namely D176 and H178. These two residues are also seen to make hydrogen bonds with TSA.

[0044] A comparison of all HDACi with TSA based on the parameters such as the number of conformations in the cluster, free energy of binding, and common hydrogen bonds reveals the following order of HDAC1 binding by the commercial HDACi.Panobinostat>Entinostat>SAHA>Ricolinostat

[0045] Among the propolis (also referred to as bee glue) derived compounds namely CAPE, CAPE-D1 , CAPE-D2 and CAPE-D3, CAPE-D3 was found to be a marginally better HDAC1 binder with 31 conformations out of 100 in the cluster, relatively lower binding energy (-10.81 Kcal / mol) sharing two similar hydrogen bonding residues as with TSA, namely D176 and H140. Furthermore, CAPE-D3 is relatively a better binder than SAHA (a standard HDACi with hydroxamic acid group) that share the same hydrogen bonding residues yet with only eight out of 100 conformations in the cluster and a very high inhibition constant of 943.01 nM.

[0046] Neither CAPE nor CAPE-D1 interact with Zn2+present in the catalytic domain of HDAC1 but CAPE-D1 is still identified, in one embodiment of the present invention, to have better HDAC1 binding than CAPE.

[0047] Thus, comparison of docking of all bee glue derived compounds with TSA, in terms of the number of conformations in the highest ranked cluster, binding energy values, and common hydrogen bonds (making similar interactions) reveals the following order of HDAC1 binding:CAPE-D3 >CAPE-D2>CAPE-D1 >CAPE

[0048] The molecular docking of immunomodulatory drugs (IMiDs) with the HDAC1 protein reveals a different perspective. The second generation IMiDs, Pomolidomide and Lenalidomide revealed relatively high binding energy and very low number of conformations in the highest ranked cluster, such as -8.95 Kcal / mol, six conformations out of 100 and -8.88 Kcal / mol, nine conformations out of 100, respectively.

[0049] Also, IMiDs did not interact with Zn nor shared any common hydrogen bonding residues with the HDACi TSA. Hence, IMiDs may exhibit a different mechanism of HDAC1 binding than TSA.

[0050] Referring to FIG. 6, in a human, non-Hodgkin lymphoma cell line, CAPE-D3 exhibited a high lymphoma cell growth inhibitory potential (82.4±5.7) than its parent compound, CAPE (60.7±8.9%). CAPE-D3 showed a comparable lymphoma cell growth inhibition with the nonspecific HDAC1 inhibitors / standard pan-HDAC inhibitors namely SAHA (82.0±3.8%) and a slightly less growth inhibitory ability than TSA (92.1 ±1 .4) in the same human non-Hodgkin lymphoma cell line.

[0051] Referring to FIG. 7, in another non-Hodgkin lymphoma cell line (human), CAPE-D3 exhibited an IC 50 value of 5.25 pM further confirming its remarkable and surprising lymphoma growth inhibitory ability.References:Sunghwan Kim et al., PubChem in 2021 : new data content and improved web interfaces, Nucleic Acids Research, Volume 49, Issue D1 , 8 January 2021 , Pages D1388- D1395, https: / / doi.Org / 10.1093 / nar / gkaa971Sadowski Jen et al., Comparison of Automatic Three-Dimensional Model Builders Using 639 X-ray Structures, Journal of Chemical Information and Computer Sciences 1994 34 (4), 1000-1008; https: / / doi.org / 10.1021 / ci00020a039O'Boyle NM et al. Open Babel: An open chemical toolbox. J Cheminform 3, 33 (2011). https: / / doi.Org / 10.1186 / 1758-2946-3-33Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 2011 Oct 24;51 (10):2778-86. https: / / doi.Org / 10.1021 / ci200227u

Claims

I CLAIM:1 . A method for inhibiting the proliferation or growth of or eliminating one or more cells that express HDAC1 comprising: contacting the one or more cells with an effective amount of a CAPE derivative selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2- phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

2. The method of claim 1 wherein the CAPE derivative selectively inhibits the level and / or activity of HDAC1 .

3. The method of claim 1 or claim 2, wherein the one or more cells express HDAC1 dysregulation.

4. The method of claim 3, wherein the dysregulation is overproduction of HDAC1 .

5. The method of claim 3, wherein the dysregulation is high HDAC1 activity.

6. The method of any one of claims 1 to 5, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

7. The method of any one of claims 1 to 5, wherein the CAPE derivative is 3,4- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate.

8. The method of any one of claims 1 to 5, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate.

9. The method of any one of claims 1 to 8, wherein the CAPE derivative is at a concentration of 1 pM to 10 pM.

10. The method of any one of claims 1 to 8, wherein the CAPE derivative is at a concentration of 5 pM to 10 pM.11 . The method of any one of claims 1 to 8, wherein the CAPE derivative is at a concentration of 2.5 pM to 5 pM.

12. A method for treating a tumor comprising cells that express HDAC1 , the method comprising: administering to an individual in need of treatment for the tumor an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester I (E)-2- phenylethyl 3-(2,5-dihydroxyphenyl)acrylate.

13. The method of claim 12, wherein the agent selectively inhibits the level and / or activity of HDAC1.

14. The method of claim 12 or claim 13, wherein the one or more cells express HDAC1 dysregulation.

15. The method of claim 14, wherein the dysregulation is overproduction of HDAC1.

16. The method of any one of claims 12 to 15, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

17. The method of any one of claims 12 to 15, wherein the CAPE derivative 3,4- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate.

18. The method of any one of claims 12 to 15, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate.

19. A method for treating a disease condition that expresses dysregulation HDAC1 , the method comprising: administering to an individual in need of treatment for the disease condition an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester I (E)-2- phenylethyl 3-(2,5-dihydroxyphenyl)acrylate.

20. The method of claim 19, wherein the agent selectively inhibits the level and / or activity of HDAC1.21 . The method of claim 19, wherein the dysregulation is overproduction of HDAC1 .

22. The method of any one of claims 19 to 21 , wherein the CAPE derivative is 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

23. The method of any one of claims 19 to 21 , wherein the CAPE derivative is 3,4- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate.

24. The method of any one of claims 19 to 21 , wherein the CAPE derivative is 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate.

25. The method of any one of claims 1 to 24, wherein the disease condition is selected from the group consisting of lymphoma, peripheral t-cell lymphoma and extranodal nk / t-cell lymphoma with HDAC1 dysregulation.

26. The method of any one of claims 1 to 24, wherein the disease condition is hormone refractory prostate cancer with HDAC1 dysregulation.

27. The method of any one of claims 1 to 24, wherein the disease condition is acute myeloid leukemia with HDAC1 dysregulation.

28. The method of any one of claims 1 to 24, wherein the disease condition is selected from the group consisting of temozolomide resistant glioma, neurodegenerative disorders with HDAC1 overexpression and high activity, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease.

29. The method of any one of claims 1 to 24, wherein the disease condition is selected from the group consisting of Inflammatory disorders, inflammatory bowel disease, asthma, rheumatoid arthritis and allergic rhinitis, atopic dermatitis with HDAC1 dysregulation.

30. The method of any one of claims 19 to 29, wherein the agent is at a concentration of 1 pM to 10 pM.31 . The method of any one of claims 19 to 29, wherein the agent is at a concentration of 5 pM to 10 pM.

32. The method of any one of claims 19 to 29, wherein the agent is at a concentration of 2.5 pM to 5 pM.

33. Use of an effective amount of an agent selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3- phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate for treating a disease condition that expresses dysregulation HDAC1.

34. The use of claim 33, where the treatment is for selective inhibition of the level and / or activity of HDAC1 .

35. The use of claim 33, wherein the dysregulation is overproduction of HDAC1 .

36. The use of any one of claims 33 to 35, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

37. The use of any one of claims 33 to 35, wherein the CAPE derivative is 3,4- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate.

38. The use of any one of claims 33 to 35, wherein the CAPE derivative is 2,5- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5- dihydroxyphenyl)acrylate.

39. The use of any one of claims 33 to 38, wherein the disease condition is selected from the group consisting of lymphoma, peripheral t-cell lymphoma and extranodal nk / t-cell lymphoma with HDAC1 dysregulation.

40. The use of any one of claims 33 to 39, wherein the disease condition is hormone refractory prostate cancer with HDAC1 dysregulation.41 . The use of any one of claims 33 to 39, wherein the disease condition is acute myeloid leukemia with HDAC1 dysregulation.

42. The use of any one of claims 33 to 39, wherein the disease condition is selected from the group consisting of temozolomide resistant glioma, neurodegenerative disorders with HDAC1 overexpression and high activity, Amyotrophic Lateral Sclerosis (ALS), and Parkinson’s disease.

43. The use of any one of claims 33 to 39, wherein the disease condition is selected from the group consisting of Inflammatory disorders, inflammatory bowel disease, asthma, rheumatoid arthritis and allergic rhinitis, atopic dermatitis with HDAC1 dysregulation.

44. The use of any one of claims 33 to 43, wherein the agent is at a concentration of 1 pM to 10 pM.

45. The use of any one of claims 33 to 43, wherein the agent is at a concentration of 5 pM to 10 pM.

46. The use of any one of claims 33 to 43, wherein the agent is at a concentration of 2.5 pM to 5 pM.

47. A selective pharmaceutical composition comprising: an effective amount of a CAPE derivative selected from the group consisting of 3,4- dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2-phenylpropyl 3-(3,4- dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-3- phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5-dihydroxycinnamic acid phenylethyl ester / (E)-2-phenylethyl 3-(2,5-dihydroxyphenyl)acrylate.And a pharmaceutically acceptable carrier.

48. The selective pharmaceutical composition of claim 47, wherein the CAPE derivative is at a concentration of 1 pM to 10 pM.

49. The selective pharmaceutical composition of of claim 47, wherein the CAPE derivative is at a concentration of 5 pM to 10 pM.

50. The selective pharmaceutical composition of claim 47, wherein the CAPE derivative is at a concentration of 2.5 pM to 5 pM.

51. The selected pharmaceutical composition of any one of claims 47 to 50 wherein the effective amount of a CAPE derivative comprises two or more CAPE derivatives selected from the group consisting of 3,4-dihydroxycinnamic acid 3-phenylpropyl ester I (E)-2- phenylpropyl 3-(3,4-dihydroxyphenyl)acrylate, 2,5-dihydroxycinnamic acid 3- phenylpropyl ester I (E)-3-phenylpropyl 3-(2,5-dihydroxyphenyl)acrylate, and 2,5- dihydroxycinnamic acid phenylethyl ester I (E)-2-phenylethyl 3-(2,5- dihydroxyphenyl)acrylate.

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