Molephantinin derivatives and uses thereof

Abstract

Disclosed are compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, and R5 are defined herein. Also disclosed are pharmaceutical compositions comprising such compounds, and medical uses of such compounds, such as treatment of cancer.

Description

MOLEPHANTININ DERIVATIVES AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of Singapore Application No. 10202402654Y, filed on 28 August 2024, which is hereby incorporated by reference in its entirety.FIELD OF INVENTION

[0002] The present invention relates generally to the field of pharmaceutical agents and, more specifically, relates to molephantinin derivatives, compositions comprising the molephantinin derivatives, and uses of such derivatives and compositions.BACKGROUND OF INVENTION

[0003] Cancer continues to be one of the leading causes of death worldwide. There are predicted to be more than 35 million cancer cases during 2050, up from the estimated 20 million in 2022, according to latest data from the International Agency for Research on Cancer (IARC), a specialized branch of the World Health Organization (WHO). The increase reflects both population ageing and growth, as well as changes in people’s exposure to risk factors.

[0004] Conventional chemotherapeutic drugs are often associated with significant drawbacks, including non-specific cytotoxicity, severe adverse effects, and the development of drug resistance. There is therefore a continued need for the discovery of therapeutic agents that are both effective and safe.

[0005] Natural products have long been recognized as an important source of therapeutic agents for cancers. Plant-derived compounds, in particular, have played a significant role in the development of anti-cancer drugs due to their structural diversity and biological activity Beyond pharmaceutical use, such compounds are also increasingly being studied and commercialized as functional ingredients in health supplements, especially when they exhibit bioactivity at sub-pharmacological doses.

[0006] With rising consumer interest in preventive healthcare and complementary therapies, compounds that exhibit bioactivity against cancer-related pathways, while also possessing favorable safety profiles and being derived from natural sources, may serve both as medicaments for cancer treatment and as health supplements for preventive or supportive care in cancer patients.

[0007] However, many natural compounds with potential anti-cancer effects remain underexplored or poorly characterized in terms of their pharmacological profiles and mechanisms of action. In addition, efforts to modify these compounds to improve their bioavailability, potency, or specificity remain limited.

[0008] Accordingly, there is a need for novel bioactive compounds derived from natural sources that exhibit anti-cancer properties and are suitable for development as both pharmaceutical agents and health supplements.SUMMARY OF INVENTION

[0009] In one aspect, the present disclosure refers to a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof, wherein R1to R5are each independently selected from the group consisting of H, halo, CF3, SO2F, and NO2.

[0010] In another aspect, the present disclosure refers to a pharmaceutical composition comprising the compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, the present disclosure refers to the compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

[0012] In another aspect, the present disclosure refers to use of the compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0013] In another aspect, the present disclosure refers to the compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

[0014] In yet another aspect, the present disclosure refers to a method of treating cancer in a subject, wherein the method comprises administering an effective amount of the compound as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, to the subject.DESCRIPTION OF FIGURES

[0015] The accompanying figures illustrate disclosed embodiments of the invention and serve to explain the principles of the disclosed embodiments. It is to be understood, however, that the figures are designed for purposes of illustration only, and not as a definition of the limits of the invention.

[0016] Figures 1A- 1G show line graphs ofthe cell viability (%) of DLD-1 cells plotted against the log concentration (pM) of compounds NYH101 -- NYH107, as determined by a 48-hour MTT assay. ECS0values are indicated on the graphs. Error bars denote standard deviations. The results demonstrate that compounds NYH101 - NYH107 exhibit dose-dependent cytotoxic effects on DLD-1 cells.

[0017] Figures 2A - 2C show representative images and quantification results of a colony formation assay following treatment with NYH101 and NYH102 at various concentrations for 1 hour and allowed to grow for 7 days. *P < 0.05, "P < 0.01 ,< 0.001 and< 0.0001 . Error bars denote standard deviations. The results demonstrate that compounds NYH101 and NYH102 induce a dose-dependent reduction in DLD-1 colony count and area. Figure 2D shows line graphs depicting tumor volume following intratumoral injection of either vehicle or 25 mg / kg of compound NYH101 in nude mice subcutaneously xenografted with DLD-1 cells. Injections were administered every alternate day for a total of nine doses. Tumor volume was monitored throughout the treatment period and analysed using two-way ANOVA. Error bars denote the standard error of the mean (SEM). ~p < 0.0001. Figure 2E shows bar charts of tumor weight and volume measured at the endpoint of the experiment. Data was analysed using an unpaired Student’s t-test. Error bars denote the standard error of the mean (SEM). ***p < 0.001 . Figure 2F shows images of excised tumors collected at the experimental endpoint. Figure 2G shows the results of Western biol analysis of apoptotic markers in DLD-1 cells following 24-hour treatment with compounds NYH101 and NYH102 at various concentrations. Figure 2H shows the results of Western blot analysis of autophagy markers in DLD-1 cells following 24-hour treatment with compounds NYH101 and NYH102 at various concentrations.

[0018] Figures 3A and 3B show representative images of Transwell migration and invasion assays of DLD-1 cells captured under 20X magnification using a Zeiss Live Observer II after 24-hour treatment with NYH101 and NYH102 at various concentrations. Crystal violet staining was eluted, the absorbance measured at 595 nm was used to calculate the cell migration and invasion ratios, and the results are shown in Figure 3E. *p < 0.05; **p < 0.01 ; ***p < 0.001 ; ****p < 0 0001 . Error bars represent standard deviations. Figures 3C and 3D show representative images of Transwell migration and invasion assays of HCT116 cells captured under 20X magnification using a Zeiss Live Observer II after 24-hour treatment with NYH101 and NYH102 at various concentrations. Crystal violet staining was eluted, the absorbance measured at 595 nm was used to calculate the cell migration and invasion ratios, and the results are shown in Figure 3F. *p < 0.05; **p < 0.01 ; ***p < 0.001 ; ****p < 0.0001 . Error bars represent standard deviations. Figure 3G shows the results of Western blot analysis of epithelial-mesenchymal transition (EMT) markers in DLD-1 cells treated with compounds NYH101 and NYH102 for 24 hours. Figure 3H shows representative images of immunofluorescence staining of E-cadherin with DAPI nuclear counterstaining in PFA-fixed cells treated with 5 pM of compounds NYH101 and NYH102 for 24 hours, captured at 63X magnification using a Zeiss Live Observer II. Figure 3I show's the plot profilesdepicting the fluorescence intensity of individual channels in arbitrary units of representative cells. Figure 3J shows results of cell adhesion assay. DLD-1 cells were seeded on Matrigel and treated with various concentrations of NYH102 for 2 hours. Cell adhesion was quantified by measuring absorbance. Statistical analysis was performed using an unpaired Student’s t-test. *””'p < 0.0001 . Error bars denote the standard deviation. Figure 3K shows a Kaplan-Meier graph depicting probability of survival. A cancer metastasis model was established in Balb / cJ mice (n = 5). The mouse-origin colorectal cancer cell line CT26 was intravenously injected, and the animals were treated with four doses of vehicle or 25 mg / kg NYH102 administered every' alternate day via intraperitoneal (IP) injection. Animal survival was monitored and plotted using the Kaplan-Meier graph. Statistical analysis was conducted using the log-rank test. *p < 0.05. Figure 3L shows representative images of lung metastases. A control cull was performed, and the lungs were imaged to assess metastases. The dark grey areas in the top panel indicate lung hemorrhage, while metastatic nodules in the vehicle-treated mice are highlighted by the white box in the middle panel. A similar lung region of NYH102-treated mice is presented for comparison purposes.

[0019] Figure 4A shows representative images of immunofluorescence staining of F-actin with DAPI nuclear counterstaining in PFA-fixed cells treated with 5 pM of NYH101 and NYH102 for 24 hours, captured at 63X magnification using a Zeiss Live Observer II. Figure 4B shows representative images of an invadopodia degradation assay in DLD-1 cells treated with 0.75 pM NYH102 for 48 hours. Coversiips were coated with Oregon Green 488-conjugated gelatin, and invadopodia-mediated degradation is indicated by the loss of fluorescence. White boxes highlight examples of invadopodia- rich regions. The area of degraded gelatin per view was quantified and normalized to that of DMSO- treated controls and presented in Figure 4C. Statistical analysis was performed using an unpaired Student’s t-test. ""p < Q.00Q1 . Error bars denote the standard deviation. Figure 4D shows the results of Western blot analysis of YAP1 protein expression in DLD-1 and HCT116 cells after 24 hours of treatment with various concentrations of NYH101 and NYH102.

[0020] Figure 5A shows representative images of SYTO-14 Green staining with DAPI nuclear counterstaining in DLD-1 cells treated with 1 pM and 2.5 pM of NYH102 for 24 hours. Images 'were captured at 63X magnification using a Zeiss LSM980 confocal microscope. The fluorescence intensity was quantified in arbitrary units and is presented in Figure 5B. "P < 0.01 ; **"P < 0.0001. Error bars denote standard deviations. Figure 5C shows representative images of EU-Click-iT staining with DAPI nuclear counterstaining in DLD-1 cells treated with 2.5 pM and 5 pM of NYH102 for 1 hour and 3 hours. Images were captured at 63X magnification using a Zeiss LSM980 confocal microscope. The fluorescence intensity was quantified in arbitrary units and is presented in Figure 5D.0.0001 using unpaired Student's t-test. Figure 5E shows the results of Western blot analysis of RNA polymerase II, demonstrating the stalling effect of RNA polymerase II following treatment with 5 pM of NYH102 at various time points. Figure 5F shows representative images of immunofluorescence staining of RNA polymerase II with DAPI nuclear counterstaining in DLD-1 cells treated with 1 pM NYH102 for 24 hours, captured at 63X magnification using a Zeiss LSM980 confocal microscope. Fluorescence intensity was quantified in arbitrary units and is presented in Figure 5G. *p < 0.001.DETAILED DESCRIPTION OF INVENTION

[0021] Exemplary, nori-limiting embodiments of the present disclosure will now be described.

[0022] The present disclosure addresses the need for novel bioactive compounds derived from natural sources that exhibit anti-cancer properties and are suitable for development as both pharmaceutical agents and health supplements.

[0023] In one aspect, there is provided a compound of formula I:or a pharmaceutically acceptable salt or solvate thereof; wherein R1to R5are each independently selected from the group consisting of H, halo, CFa, SO2F, and NO2.

[0024] As used herein, the term “halo" or “halogen" refers to F, Cl, Br or I.

[0025] In some specific examples, R1 and Rs are each independently H or F.

[0026] In some specific examples, R2 and R4 are each independently selected from the group consisting of H, F, and CF3.

[0027] In some specific examples, Rs is selected from the group consisting of H, F, CF3, SO2F, and NO2.

[0028] In some specific examples, the compound of formula I is the following:

[0029] In some more specific examples, the compound of formula I is the following:

[0030] In some examples, the compounds of formula I, pharmaceutically acceptable salts or solvates thereof, are in isolated form. As used herein, the term "isolated" refers to a substance that is substantially or essentially free from components that normally accompany it in its native state.

[0031] In some examples, the compounds of formula I, pharmaceutically acceptable salts or solvates thereof, are in substantially purified form and / or in a form substantially free from contaminants. In some examples, the substantially purified form is at least about 50% by weight, at least about 60% by weight,at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, at least about 98% by weight, at least about 99% by weight, or about 100% by weight of the compounds of formula I, pharmaceutically acceptable salts or solvates thereof.

[0032] References herein (in any aspect or embodiment of the invention) to compounds of formula I includes references to such compounds per se, and to stereoisomers of such compounds.

[0033] The term “stereoisomer” as used herein refers to a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centres and other chemical structure may exist in the compounds as disclosed herein, which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of formula I and their salts, in particular pharmaceutically acceptable salts, include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture, if desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. The term “enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term “diastereomers” refers to a pair of stereoisomers that are not mirror images of each other and non- superimposable.

[0034] Geometric isomerism (also known as cis-trans isomerism or E-Z isomerism) is a specific form of stereoisomerism. The compounds as disclosed herein may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are also included within the scope of the invention.

[0035] In some examples, the compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All regioisomeric, tautomeric forms and mixtures thereof are included within the scope of the invention.

[0036] Stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques, such as chromatography or fractional crystallisation. Alternatively, the desired stereoisomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e., a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e., a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.

[0037] The term “pharmaceutically acceptable salts” as used herein includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. Such salts may be derived from mineral acids, organic acids, or metal cations. Suitable mineral acids include hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulphuric acid. Suitable organic acids include, for example, tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaricacid, benzoic acid, glycolic acid, gluconic acid (e.g., D-gluconic), succinic acid, and arylsulphonic acids such as benzenesulphonic acid and p-toluenesulphonic acid. Saits may also be formed with metals such as sodium, magnesium, or preferably, potassium and calcium.

[0038] Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulphonic acids (e.g., benzenesulphonic, naphthalene-2-sulphonic, naphthalene- 1 ,5-disulphonic and p-toluenesulphonic), ascorbic (e.g., L-ascorbic), L-aspartic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1 S)-camphor-10-sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane-1 ,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g., D-gluconic), glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g., (+)-L-lactic and (±)-DL- lactic), lactobionic, maleic, malic (e.g., (-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulphuric, tannic, tartaric (e.g., (+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

[0039] Particular examples of pharmaceutically acceptable salts of the compound of formula I are salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.

[0040] Pharmaceutically acceptable salts may be prepared by conventional methods. For example, a salt may be formed by reacting a free acid or free base form of a compound of formula I with one or more equivalents of a suitable acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques such as evaporation under reduced pressure, freeze-drying, or filtration. Alternatively, a pharmaceutically acceptable salt may be prepared by exchanging the counter-ion of an existing salt with another counter-ion using a suitable ion exchange resin.

[0041] Suitable solvates of the compound of formula I include those formed by the incorporation of molecules of a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent) into the solid-state structure (e.g., crystal structure) of the compound of formula I. Examples of suitable solvating solvents include water, alcohols such as ethanol, isopropanol, and butanol, as well as dimethylsulphoxide. The solvates may be stoichiometric or non-stoichiometric, and particularly preferred solvates are hydrates. Examples of hydrates include hemihydrates, monohydrates, and dihydrates.

[0042] Solvates may be prepared by recrystallising the compound of formula I from a solvent or mixture of solvents comprising the solvating solvent. Whether or not a solvate has been formed in any given instance may be determined by analysing crystals of the compound using standard techniques well known in the art, such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0043] in some exampies, the present disclosure aiso includes pharmaceutically functional derivatives of the compounds of formula I. Pharmaceutically functional derivatives of the compounds of formula I includes derivatives that have, or provide for, the same biological function and / or activity as any compounds of formula I. Thus, for the purposes of this disclosure, the term also includes prodrugs of the compounds of formula I.

[0044] As used herein, the term “prodrug” of a compound includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally- detectable amount, and within a predetermined time (e.g., within a dosing interval of between 6 and 24 hours (i.e., once to four times daily)).

[0045] Prodrugs of a compound may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs of the compounds of formula I include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively.

[0046] Specific examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e g. in Bundegaard, H. “Design of Prodrugs” p. I-92, Elsevier, New York-Oxford (1985).

[0047] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, are isotopically labelled. In some other examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, are not isotopically labelled.

[0048] The term "isotopically labelled” as used herein refers to a compound in which there is a nonnatural isotope (or a non-natural distribution of isotopes) at one or more positions in the compound. References herein to "one or more positions in the compound" will be understood by those skilled in the artto referto one or more ofthe atoms ofthe compound offormula I, or pharmaceutically acceptable salts or solvates thereof. Thus, the term "isotopically labelled" includes references to compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, that are isotopically enriched at one or more positions in the compound.

[0049] The isotopic labelling or enrichment of the compound of formula I, or pharmaceutically acceptable salts or solvates thereof, may be with a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and / or iodine. Particular isotopes that may be mentioned in this respect include2H,3H,11C,13C,14C,13N,15N,150,17O,180,35S,18F,37CI,77Br,82Br and125l).

[0050] When a compound is labelled or enriched with a radioactive or nonradioactive isotope, the compound that may be mentioned includes those in which at least one atom in the compound displays an isotopic distribution in which a radioactive or non-radioactive isotope of the atom in question is present in levels at least about 10% (e g., from about 10% to about 5000%, or from about 50% to about1000%, or from about 100% to about 500%) above the natural level of that radioactive or nonradioactive isotope.

[0051] Without being bound by theory, the compounds of formula I may be derivatives of molephantinin, specifically, ester derivatives of molephantinin. Molephantinin is represented by the following formula:

[0052] Thus, in some examples, the compounds of formula I may be formed using molephantinin as a starting material through an esterification reaction, in which the hydroxyl group (-OH) of molephantinin reacts with a carboxylic acid or another acylating agent, resulting in the replacement of the hydroxyl hydrogen (-H) with an acyl group (-COR) to form the ester derivatives of molephantinin. Non-limiting examples of suitable carboxylic acids include benzoic acid and substituted benzoic acids such as halobenzoic acids, halomethyl benzoic acids, halosulfonyl benzoic acids, and nitrobenzoic acids. The halogen substituent can be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), preferably fluorine (F). Non-limiting examples of suitable acylating agents include acyl halides derived from the carboxylic acids described herein. An acyl halide is a chemical compound derived from an oxoacid by replacing a hydroxyl group (-OH) with a halide group (-X, where X is a halogen). The halide group can be fluoride (F), chloride (Cl), bromide (Br), or iodide (I) group, preferably chloride (Ci) group. Depending on the desired ester derivative of molephantinin to be formed, a person skilled in the art can determine, without undue experimentation, the suitable carboxylic acid or acylating agent, together with the suitable reaction conditions, such as the temperature, pressure, suitable solvent and / or catalyst to be used.

[0053] In one aspect, there is also provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0054] The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the relevant compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. The pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no deleterious or detrimental side effects or toxicity under the conditions of use.

[0055] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.

[0056] Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington, The Science and Practice of Pharmacy, 23rd Edition (2020), Elsevier Inc.

[0057] The compounds of formula I or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical compositions comprising the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, may be administered by any suitable route, but may particularly be administered orally, intravenously, intramuscularly, intraperitoneally, cutaneously, subcutaneously, transmucosaily (e.g., sublingually or buccally), rectaily, transdermally, nasally, pulmonarily (e.g., tracheally or bronchially), intratumorally, topically, by any other parenteral route.

[0058] The compounds of formula I or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical compositions comprising the compound of formula I or a pharmaceutically acceptable salt or solvate thereof, may be formulated into a dosage form adapted for administration to the subject by the desired route of administration. Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0059] For parenteral administration, a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g., Langer, Science (1990) 249, 1527.

[0060] Otherwise, the preparation of suitable formulations may be achieved routinely by the skilled person using routine techniques and / or in accordance with standard and / or accepted pharmaceutical practice.

[0061] The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient, i.e., the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. For example, a solid oral composition may be formulated in a dosage unit such as a tablet or capsule that may contain from 1 to 99 % (w / w) active ingredient, from 0 to 99% (w / w) diluent or filler, from 0 to 20% (w / w) of a disintegrant, from 0 to 5% (w / w) of a lubricant, from 0 to5% (w / w) of a flow aid, from 0 to 50% (w / w) of a granulating agent or binder, from 0 to 5% (w / w) of an antioxidant, and from 0 to 5% (w / w) of a pigment. A controlled release tablet may in addition contain from 0 to 90 % (w / w) of a release-controlling polymer. A parenteral formulation, such as a solution or suspension for injection or a solution for infusion, may contain from 1 to 50 % (w / w) active ingredient, from 50% (w / w) to 99% (w / w) of a liquid or semisolid carrier or vehicle (e.g., a solvent such as water), and from 0 to 20% (w / w) of one or more other excipients such as buffering agents, antioxidants, suspension stabilisers, tonicity adjusting agents and preservatives.

[0062] Compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may also be presented as a “food” or as a “supplement”. The term “food” is used in a broad mannerto referto edibles for consumption, for example as a food ingredient, or a food product in liquid or solid form. As a “supplement”, compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may be taken as a food supplement, for example as a nutritional supplement.

[0063] In another aspect, there is provided the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use in therapy.

[0064] In another aspect, there is provided the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use in the treatment of cancer.

[0065] In another aspect, there is provided use of the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of cancer.

[0066] In yet another aspect, there is provided a method of treating cancer in a subject, wherein the method comprises administering a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, to the subject.

[0067] As used herein, the term “treating” or “treatment” covers the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease state from occurring in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) relieving the disease state, i.e., causing regression of the disease state. For the avoidance of doubt, the term also includes references to amelioration of symptoms, therapeutic, curative or palliative treatment of subjects in need of such treatment, as well as to the prophylactic treatment and / or diagnosis of subjects which are susceptible to the relevant disease states. Specifically, the term “treating” or “treatment” includes and may be observed in prevention of dysregulated cellular or tumoral growth, inhibition of cell migration and / or invasion, reduction in tumor size and / orthe number of tumors, induction of cancer cell apoptosis, autophagy, and / or other cell death, and / or prevention of relapse. Efficacy of treatment may be expressed in as a ratio or percentage (%) increase or decrease relative to a control untreated sample or group. This may further be expressed in fluorescence intensity as arbitrary units relative to the control untreated sample or group.

[0068] In some specific examples, the treating of cancer comprises inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell invasion; ameliorating the symptoms of cancer; reducing the size of a cancer tumor; reducing the number of cancer tumors; reducing the number of cancer cells; inducing cancer cell necrosis, pyroptosis, oncosis, apoptosis, autophagy, or other cell death.

[0069] As used herein, the term “subject” is used interchangeably with the term “patient" to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some examples, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other examples, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

[0070] The term “therapeutically effective amount” as used herein refers to an amount of a compound as disclosed herein, alone or in combination with other active ingredients, sufficient to effect a therapeutic response (e.g., to treat or prevent the disease) in the subject over a reasonable timeframe. The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect). Efficacy can also be expressed as a “fold” increase or decrease relative to a control sample or group. For example, a therapeutically effective amount can effect a therapeutic response of a 1.25-fold, 1.5-fold, 2-fold, 5-fold increase or decrease over the control.

[0071] The selection of the exact dose and the most appropriate delivery regimen will be influenced by inter alia the pharmacological properties of the compound and pharmaceutical composition, such as the potency and the pharmacodynamic characteristics of the particular compound; the nature, stage, and severity of the disease, condition, or symptoms being treated; the species, age, gender, physical health, mental health, medical condition, and weight of the subject; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the subject, the effect desired, etc. In any event, the amount of compound of formula I, ora pharmaceutically acceptable salt or solvate thereof, in the composition or to be administered to the individual subject, which will be most suitable for the subject, may be determined routinely by the medical practitioner, or other skilled person.

[0072] By way of general guidance, the daily oral dosage of the active ingredient, i.e., the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, will range between about 0.001 to about 5000 mg per day, or between about 0.01 to about 1000 mg per day, or between about 0.1 to about 250 mg per day. Intravenously, the doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. Administration may be continuous or intermittent (e g., by bolus injection). The dosage may also be determined by the timing and frequency of administration. For example, the compound of formula I, or pharmaceutically acceptable salts or solvates thereof, may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. The above-mentioned dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0073] As used herein, the term “cancer” refers to a condition whereby cells are characterized by dysregulated growth and proliferation that have the potential to invade surrounding tissues and / or metastasize to other organs. In some examples, the cancer is one or more selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumors, CNS tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, rectum cancer, colorectal cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e g., acute lymphocytic, acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (e g., small cell or non-small cell), lung carcinoid tumor, lymphoma (e.g., of the skin), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor. In some specific examples, the cancer is colorectal cancer.

[0074] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, are cytotoxic, and induce cytotoxicity in cells, in particular cancer cells. Thus, in some examples, there is provided a method of inducing cytotoxicity in cells, by contacting the cells with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The term "cytotoxic" or grammatical variants thereof refer to a substance or process that causes cell death, in particular apoptotic cell death (i.e., apoptosis) in the context of cancer cell death.

[0075] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, exhibit cytostatic activity, and induce cytostasis in cells, particularly in cancer cells. Thus, in some examples, there is provided a method of inducing cytostasis in cells, by contacting the cells with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The term "cytostatic" or grammatical variants thereof refer to a substance or process that inhibits cell growth, division, and / or multiplication without necessarily causing cell death.

[0076] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, can be both cytotoxic and cytostatic.

[0077] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, activate apoptosis pathway(s), by for example, increasing the expression of apoptotic protein(s). Thus, in some examples, there is provided a method of activating the apoptosis pathway of a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some other examples, there is provided a method of increasing the expression of apoptotic protein in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvates thereof. The term “apoptotic proteins” refers to proteins that play a crucial role in regulating apoptosis. Non limiting examples of apoptotic proteins include caspases and poly(ADP-ribose) polymerases (“PARP”). Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in apoptosis. Caspases are synthesized as inactive precursors called pro-caspases. Activation typically involves proteolytic cleavage, where specific enzymes cleave the procaspase at particular sites, releasing the active enzyme. Activated caspases consist of a large and a small subunit that together form the active site. Thus, the presence of cleaved caspases indicate that the caspases are activated. There are two main categories of caspases involved in apoptosis: initiator caspases (e.g., caspase-2, - 8, -9, -10) and effector caspases (e.g., caspase-3, -6, -7). In some specific examples, the compounds of formula I activate caspase-3, -7, -8. PARPs are a family of proteins that participate in caspasedependent apoptosis by being cleaved by caspases during the apoptotic process. The cleavage of a specific PARP, PARP-1 , by caspases results in the formation of a characteristic 89 kDa fragment. The 89 kDa fragment can be released into the cytoplasm where it can interact with apoptosis-inducing factor (AIF) to facilitate the apoptotic process. Thus, in some specific examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, activate PARP-1 by cleaving PARP-1 to form an 89 kDa fragment.

[0078] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, activate autophagy pathway(s). Thus, in some examples, there is provided a method of activating the autophagy pathway of a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The term “autophagy” refers to the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. The activation of autophagy pathway(s) can be detected by the detection of autophagy markers. Non limiting examples of autophagy markers include LC3 (microtubule-associated protein 1 light chain 3), p62 / SQSTM1 , and Beclin-1.

[0079] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, induce cytotoxicity in cells by activating the apoptosis pathway(s). In some other examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, induce cytotoxicity in cells by activating the autophagy pathway(s). In some other examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, induce cytotoxicity in cells by activating both the apoptosis pathway(s) and autophagy pathway(s).

[0080] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may reduce the clonogenicity of a cell, in particular a cancer cell. Thus, in some examples, there is provided a method of reducing the clonogenicity of a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The term “clonogenicity” refers to the ability of a single cell to proliferate and form a colony of genetically identical cells. It is generally used to describe a cell's capacity for self-renewal and expansion.

[0081] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may inhibit cancer cell metastasis. Thus, in some examples, there is provided a method of inhibiting cancer cell metastasis, by contacting the cancer cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0082] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may inhibit cell migration, in particular cancer cell migration. Thus, in some examples, there is provided a method of inhibiting cell migration, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salts or solvate thereof. Cancer cell migration, a crucial step in metastasis, involves cancer cells detaching from the primary tumor and moving to other parts of the body.

[0083] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may inhibit cancer cell invasion. Thus, in some examples, there is provided a method of inhibiting cancer cell invasion, by contacting the cancer cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Cancer cell invasion is the process where malignant tumor cells penetrate and migrate into surrounding tissues, breaking through the basement membrane and extracellular matrix. It is a crucial step in cancer progression and metastasis, enabling cancer cells to spread to other parts of the body.

[0084] In general, cancer ceil migration and invasion involve complex mechanisms such as individual cell migration, collective ceil migration, epithelial-mesenchymal transition (EMT), and extracellular matrix degradation. Cancer cells can migrate individually, utilizing cytoskeletal changes and interactions with the extracellular matrix (ECM). Cancer cells can also migrate in groups, maintaining cell-cell adhesions and exhibiting coordinated movement. This mode can involve cells moving as narrow strands or broad sheets. EMT is a crucial process where cancer cells lose their epithelial characteristics and gain mesenchymal features, becoming more motile and invasive in extracellular matrix degradation, cancer cells release enzymes that break down the ECM, creating pathways for migration and invasion.

[0085] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may reduce the expression of actin. Thus, in some examples, there is provided a method of reducing the expression of actin in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Actin is a highly conserved protein that can be present as either a free monomer called G-actin (globular actin) or as part of a linear polymer microfilament called F-actin (filamentous actin). F-actin is a key component of the cytoskeleton, which plays a vital role in generating the forces needed for cell movement. In some specific examples, the compounds of formula I may reduce the expression of F-actin.

[0086] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may reduce the expression of YAP1. Thus, in some examples, there is provided a method of reducing the expression of YAP1 in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. YAP1 , also known as Yes-associated protein 1 , is a key regulator of F-actin organization, primarily through its role in mechanotransduction and cytoskeletal feedback signaling. YAP1 and F-actin are interconnected components of cellular signaling pathways involved in mechanotransduction, cell growth, and development. YAP1 activity is influenced by the state of F-actin, and conversely, YAP1 can regulate F-actin organization. Changes in F-actin dynamics, such as stabilization ordisruption, can significantly affect the localization and activity ofYAPI .For instance, stabilization of F-actin often promotes YAP1 activation, whereas disruption of F-actin can lead to its inactivation.

[0087] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof I may reduce the expression of cortactin. Thus, in some examples, there is provided a method of reducing the expression of cortactin in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. Cortactin is a class II nucleation promoting factor (NPF) that binds to and stabilizes Arp2 / 3-mediated branch points on actin filaments. This stabilization is crucial for the formation of branched actin networks, which are important for cell motility and other dynamic processes. Cortactin is localized in areas of active cell movement, such as lamellipodia, and is involved in regulating cell migration. It contributes to the formation and dynamics of invadopodia, specialized structures that cancer cells use to degrade the extracellular matrix and invade surrounding tissues. Cortactin overexpression has been observed in many cancers and is associated with increased cell invasion and metastasis.

[0088] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may increase the expression of E-cadherin. Thus, in some examples, there is provided a method of increasing the expression of E-cadherin in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. E-cadherin is a transmembrane protein that mediates cell-cell adhesion by binding to other E-cadherins on adjacent cells, forming tight junction complexes. This adhesive function is critical for maintaining the structural integrity of epithelial tissues. E-cadherin acts as a tumor suppressor by inhibiting cell proliferation, migration, and invasion. Loss of E-cadherin expression is often associated with increased cancer cell motility, invasion, and metastasis.

[0089] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may reduce the expression of other pro-metastatic proteins. Non limiting examples of such pro-metastatic proteins include MMP9 and vimentin. Thus, in some examples, there is provided a method of reducing the expression of MMP9 in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In some other examples, there is provided a method of reducing the expression of vimentin in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. MMP9, or matrix metalloproteinase- 9, is an enzyme that plays a crucial role in breaking down extracellular matrix components and is involved in cancer progression including tumor growth, invasion, and metastasis. Vimentin is a structural protein found in the cytoskeleton of many cell types. It is a type III intermediate filament that plays a crucial role in maintaining cell structure and function. Vimentin is a key marker for EMT, a process where epithelial cells transform into mesenchymal cells, which is important in cancer progression.

[0090] In some examples, the compounds of formula I, or pharmaceutically acceptable salts or solvates thereof, may affect cellular transcription activity in a cell. In some specific examples, the compounds of formula I may reduce cellular transcription activity in a cell, in particular a cancer cell. Thus, in some examples, there is provided a method of reducing transcription in a cell, by contacting the cell with a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. In someexamples, the cellular transcription activity affected or reduced by the compounds of formula I are mediated by RNA polymerase II.

[0091] RNA polymerase II (RNAP II) is an enzyme found in the nucleus of eukaryotic cells. It is responsible for transcribing DNA into messenger RNA (mRNA) precursors, as well as certain small nuclear RNAs (snRNAs) and microRNAs (miRNAs). RNAP II is involved in all three stages of transcription, namely initiation, elongation, and termination. Reduced RNAP II activity can lead to decreased gene expression and cellular dysfunction.

[0092] In some examples, reduced cellular transcription activity the compounds of formula I may be reflected in the reduced total nucleic acid, reduced precursor mRNA (pre-mRNA), and / or reduced mRNA, and may be easily measured by a person skilled in the art without undue experimentation. A precursor mRNA (pre-mRNA) is an immature form of messenger RNA (mRNA) synthesized during transcription in eukaryotic cells. It contains both coding regions (exons) and non-coding regions (introns). Before becoming mature mRNA, pre-mRNA undergoes several processing steps, including splicing, 5' capping, and 3' polyadenylation.

[0093] Without being bound by theory, the reduced RNAP II activity may be caused by post- translational modifications to the RNAP which caused inactivation of RNAP II and / or re-localization of RNAP II to the cytoplasm.

[0094] The methods as described herein can be in vitro, in vivo, or ex vivo. When the method is an in vivo method, the method may comprise administering a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, to a subject, such as a human subject.

[0095] The terms “increase”, “induce” and grammatical variants thereof refers to the increase after treating or contacting with the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as compared to an untreated cell or subject. Similarly, the terms “inhibit”, “reduce”, “ameliorate” and grammatical variants thereof refers to the reduction after treating or contacting with the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as compared to an untreated cell or subject. In some examples, the increase or induction is about 5% to about 200%, or about 10% to about 190%, or about 20% to about 180%, or about 30% to about 170%, or about 40% to about 160%, or about 50% to about 150%, or about 60% to about 140%, or about 70% to about 130%, or about 80% to about 120%, or about 90% to about 110%, or at least about 5, 10, 15, 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, 180, 185, 190, 195 or 200% increase, as compared to the untreated cell or subject. In some examples, the inhibition, reduction, or amelioration is about 5% to about 95%, or about 10% to about 90%, or about 15% to about 85%, or about 20% to about 80%, or about 25% to about 75%, or about 30% to about 70%, or about 35% to about 65%, or about 40% to about 60%, or about 45% to about 55%, or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% inhibition, reduction, or amelioration, as compared to the untreated cell or subject.

[0096] The compounds, compositions, methods, and uses as disclosed herein may offer advantages in the treatment of the conditions disclosed herein. For example, they may be more convenient for the physician and / or patient, more efficacious, less toxic, more selective, have a broader range of activity, be more potent, produce fewer side effects, or possess other desirable pharmacological propertiescompared to similar compounds, combinations, methods, treatments, or uses known in the prior art for treating such conditions or otheiwise.

[0097] As used herein, the term “comprise”, “comprising”, or other grammatical variants, may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the term “comprising” may also relate to the situation where only the components / features listed are intended to be present (e.g., the term “comprising” may be replaced by the phrases “consisting of’ or “consisting essentially of’). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the term “comprising” and synonyms thereof may be replaced by the phrase “consisting of’ or the phrase “consisting essentially of’ or synonyms thereof and vice versa.

[0098] As used herein, the term “consist of’, "consisting of’, or other grammatical variants, may be interpreted as requiring the features mentioned, and limiting the presence of other features.

[0099] The term “consists essentially of’, "consisting essentially of’, or other grammatical variants, may be interpreted as requiring the features mentioned, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements

[0100] Depending on the context, the term “consists essentially of, "consisting essentially of, or other grammatical variants, may also referto a material where minor impurities may be present. For example, the material may be greater than or equal to about 90% pure, such as greater than about 95% pure, such as greater than about 97% pure, such as greater than about 99% pure, such as greater than about 99.9% pure, such as greater than about 99.99% pure, such as greater than about 99.999% pure, such as about 100% pure.

[0101] The invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including”, “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[0102] As used in this application, the singular form “a”, “an”, and “the” include plurai references unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes mixtures of two or more such compounds, reference to “a composition” includes mixtures of two or more such compositions, and the like.

[0103] As used herein, the term “about”, in the context of concentrations of components of the formulations, typically means + / - 5% of the stated value, more typically + / - 4% of the stated value, more typically + / ■ 3% of the stated value, more typically, + / - 2% of the stated value, even more typically + / - 1 % of the stated value, and even more typically + / - 0.5% of the stated value.

[0104] As used herein, the percentage (%) can refer to “% (w / v)" (percent weight to volume), “% (v / v)” (percent volume to volume), or “% (w / w)” (percent weight to weight), unless specified otherwise.

[0105] Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0106] The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings failing within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject mater from the genus, regardless of whether or not the excised material is specifically recited herein.

[0107] Other embodiments are within the following claims and non-limiting examples. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.EXAMPLES

[0108] Non-limiting examples of the invention and a comparative example will be further described in greater detail by reference to specific examples, which should not be construed as in any way limiting the scope of the invention.

[0109] Example 1. Extraction and purification of molephantinin

[0110] Molephantinin was extracted and purified from the leaves of Elephantopus tomentosus L. Fresh leaves of E. tomentosus L. were collected, lyophilized, and subsequently ground into powders. These leaf powders served as the starting material for extraction, using ethyl acetate as the solvent. After extraction, the mixture was centrifuged to separate the insoluble residue and pellet from the soluble crude extract. The soluble crude extract was then subjected to concentration and purification steps. Silica gel and flash column chromatography were employed to further isolate molephantinin in a purified form.

[0111] Molephantinin is referred to hereinafter as NYH101.

[0112] PCT / SG2024 / 050568 describes the synthesis of molephantin NYH001 and its derivatives. The disclosure of the PCT application is incorporated herein by reference to its entirety.

[0113] Example 2. Extraction of pure molephantinin (NYH101) from a mixture of molephantin (NYH001) and molephantinin (NYH101)

[0114] The mixture of inseparable molephantin NYH001 and molephantinin NYH101 solids which were collected previously, was further purified by gel permeation chromatography (Model: LaboACE LC-5060;Column used: JAIGEL-2HR-40; Injection concentration: 24 mg / mL; Injection volume: 10 mL; Flow rate: 30 mL / min) to give two different fractions: pure molephantinin NYH101 as a white solid (200 mg, 0.55 mmol) and a mixture of inseparable molephantinin NYH101 and molephantin NYH001.molephantin (NYH0Q1)

[0115] Example 3. Synthesis of molephantinin derivatives NYH102 - NYH107

[0116] Derivatives of molephantinin were synthesized by esterification reactions exemplified as follows:

[0117] Synthesis of NYH102 (Scheme 1)

[0118] Benzoyl chloride (10 pL, 0.083 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (15.1 mg, 0.042 mmol, 1.0 equiv), DMAP (0.05 mg, 4.19 pmol, 10 mol%), and triethylamine (30 pL, 0.25 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It was subsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(10 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH102 (17.2 mg, 0.037 mmol, 88%) as a white solid.

[0119] Synthesis of NYH103 (Scheme 2)Scheme 2

[0120] Pentafluorobenzoyl chloride (10 pL, 0.070 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (12.7 mg, 0.035 mmol, 1.0 equiv), DMAP (0.4 mg, 3.52 pmol, 10 mol%), and triethylamine (30 pL, 0.21 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It was subsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(5 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH103 (18.1 mg, 92%) as a white solid.

[0121] Synthesis of NYH104 (Scheme 3)Scheme 3

[0122] 4-(Trifluoromethyl)benzoyl chloride (10 pL, 0.065 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (11.8 mg, 0.033 mmol, 1.0 equiv), DMAP (0.4 mg, 3.27 pmol, 10 mol%), andtriethylamine (30 pL, 0.20 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It was subsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(5 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH104 (16.7 mg, 96%) as a white solid.

[0123] Synthesis of NYH105 (Scheme 4)Scheme 4

[0124] 3,5-Bis(trifluoromethyl)benzoyl chloride (10 pL, 0.04 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (7.2 mg, 0.02 mmol, 1.0 equiv), DMAP (0.2 mg, 2.0 pmol, 10 mol%), and triethylamine (16 pL, 0.12 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It was subsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(5 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgS04, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH105 (10.2 mg, 85%) as a white solid.

[0125] Synthesis of NYH106 (Scheme 5)Scheme 5

[0126] 4-(Fluorosulfonyl)benzoyl chloride (16.8 mg, 0.08 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (13.6 mg, 0.04 mmol, 1.0 equiv), DMAP (0.4 mg, 3.77 pmol, 10 mol%), and triethylamine (30 pL, 0.23 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It wassubsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(5 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH106 (17.0 mg, 82%) as a white solid.

[0127] Synthesis of NYH107 (Scheme 6)Scheme 6

[0128] Oxalyl chloride (85 pL, 0.99 mmol, 1 .5 equiv) was slowly added to a mixture of 4-nitrobenzoic acid (110 mg, 0.67 mmol, 1.0 equiv) and 3 drops of DMF in anhydrous CH2CI2at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to afford 4- nitrobenzoyl chloride (121 mg, 0.65 mmol, 99%) as a white solid.

[0129] 4-Nitrobenzoyl chloride (13.8 mg, 0.07 mmol, 2.0 equiv) was slowly added to a mixture of NYH101 (13.4 mg, 0.04 mmol, 1 .0 equiv), DMAP (0.4 mg, 3.72 pmol, 10 mol%), and triethylamine (30 pL, 0.22 mmol, 6.0 equiv) in anhydrous CH2CI2(1 mL) at 0 °C under an argon atmosphere. The reaction mixture was then warmed to room temperature and stirred for 1 hour. It was subsequently concentrated in vacuo. The crude residue was washed with saturated NaHCO3(5 mL) and extracted with dichloromethane (3 X 10 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered, and carefully concentrated in vacuo. The resulting crude material was purified by flash column chromatography on silica gel (n-hexane:EtOAc = 75:25) to afford NYH107 (17.1 mg, 90%) as a white solid.

[0130] Example 4. Evaluation of anticancer activity of NYH101 and its derivatives NYH102- NYH107in vitro

[0131] NYH101 - NYH107 exhibited anticancer and cytotoxic properties

[0132] To test the cytotoxic effect of the compound NYH101 and its derivatives NYH102-NYH107, a total of 1 ,100 human colorectal adenocarcinoma cell line DLD-1 cells were treated for 48 hours with various concentrations ranging from 0.015 pM to 15 pM, and cell viability was assessed using the MTT assay. At the end of the experiment, cells were incubated with 0.05 mg / mL MTT for 4 hours to allow the formation of formazan crystals in metabolically active cells. The crystals were then dissolved in 10% SDS in 0.01 M HCI, and absorbance was measured at 570 nm using a plate reader. The ECso values, representing the concentration at which 50% cell death occurred, were calculated using GraphPad Prism and are presented in Table 1 . All compounds showed a dose-dependent cytotoxic effect on the cells (Figures 1A-1G). Other than NYH106, all derivatives demonstrated lower ECso values comparedto NYH101 , indicating enhanced cytotoxic activity. The results show that the natural compound NYH101 and its derivatives exhibited anticancer and cytotoxic activities against the human colorectal adenocarcinoma cell line DLD-1.7Table 1. EC so 95% Cl) of compounds NYH101 to NYH107

[0133] NYH101 and NYH102 inhibited cell proliferation and clonogenicity while activating cell death pathways

[0134] A colony formation assay was conducted to further investigate the effects of NYH101 and NYH102 on the proliferative and clonogenic potential of cancer cells. A total of 1 ,000 cells were seeded and treated for 1 hour with NYH101 and NYH102 at various concentrations, followed by 7 days of growth in fresh media to allow for cell replication, proliferation, and the formation of individual colonies. The colonies were subsequently fixed with 4% PFA and stained with 0.5% (w / v) crystal violet for imaging and quantification using Imaged plugins.

[0135] A 1-hour treatment with NYH101 and NYH102 significantly decreased both the number and area of colonies formed by the cells in a dose-dependent manner. NYH102 exhibited a stronger inhibitory effect on cell proliferation, resulting in a complete absence of colony formation at 5 pM (Figures 2A - 2C).

[0136] An in vivo assessment of NYH101 was conducted using a cancer xenograft model at a dosage of 25 mg / kg. NYH101 was administered via intratumoral injection every alternate day for a total of nine doses. This treatment regimen effectively inhibited the growth of subcutaneously xenografted DLD-1 tumors throughout the study period, with a reduction in tumor size observed at the study endpoint (Figure 2D). Tumor size and weight at the endpoint were measured after the mice were sacrificed, and NYH101 -treated tumors exhibited a significant reduction compared to the vehicle-treated group (Figures 2E and 2F).

[0137] Cell death pathways, including apoptosis and autophagy, were investigated using Western blot to assess the expression of signature protein markers. Apoptotic markers such as cleaved caspase-3, -7, -8, and cleaved PARP all exhibited increased expression following 24-hour treatment with NYH101 and NYH102 in a dose-dependent manner (Figure 2G). Notably, NYH102 induced apoptosis at a lower concentration (2.5 pM) compared to NYH101 , consistent with its higher potency. Autophagy markers, including LC3B and p62, were also examined. LC3B displayed increased expression with a concurrent decreasing trend in p62 levels in a dose-dependent manner, suggesting activation of the autophagy pathway after 24-hour treatment with both NYH101 and NYH102 (Figure 2H). These findings indicate that multiple cell death pathways, including apoptosis and autophagy, may contribute to the cytotoxic effects of NYH101 and NYH102.

[0138] NYH101 and NYH102 inhibited cell migration and invasion, likely associated with impaired cytoskeleton structures

[0139] Metastatic colorectal cancer is associated with significantly lower survival rates in clinical settings, prompting investigation into whether treatment with the compounds could interfere with cancer cell metastasis.

[0010] Transwell assays were employed to assess the in vitro migratory and metastatic potential of cancer cells. The Transwell migration assay evaluates the ability of cells to migrate through a semi- permeable membrane toward a chemoattractant. In this study, 150,000 DLD-1 cells were seeded into Transwell inserts containing serum-free media supplemented with various concentrations of the test compounds. The bottom chamber contained 10% FBS-supplemented media to attract cell migration. After the migration period, cells that had traversed the membrane were fixed with 4% PFA, stained with 0.5% (w / v) crystal violet, imaged, and subsequently eluted using 33% acetic acid. Absorbance was measured at 595 nm to quantify the relative number of migrated cells.

[0141] A dose-dependent inhibition of cell migratory ability was observed in both NYH101 - and NYH102-treated DLD-1 and HCT116 colorectal cancer cells at sub-lethal doses, with NYH102 demonstrating a more potent inhibitory effect in both cell lines (Figures 3A-3F). In addition, a Transwell invasion assay was performed using a Matrigel-coated semi-permeable membrane. Matrigel simulates an extracellular matrix environment that can be degraded by cancer cells, serving as an indicator for cell invasive ability. Consistent with the results of the migration assay, the invasion assay also revealed a dose-dependent inhibition of cell invasiveness (Figures 3A-3F). These findings collectively indicate that both cellular migratory and invasive abilities were inhibited, potentially reducing the metastatic capability of the cancer cells.

[0142] The expression of key epithelial-mesenchymal transition (EMT) markers was investigated using Western blot analysis. E-cadherin, a cell adhesion protein located at tight junction complexes, exhibited significant upregulation in a dose-dependent manner following treatment with both NYH101 and NYH102 at various concentrations (Figure 3G). This upregulation was further validated through immunofluorescence staining, where treated cells displayed notably stronger E-cadherin signal intensities after 24 hours of treatment with 5 pM of the compounds (Figures 3H and 31). Additionally, pro-metastatic proteins such as MMP9 and vimentin exhibited dose-dependent reductions following treatment (Figure 3G). These findings further support the conclusion that NYH101 and NYH102 reduce the metastatic potential of cancer cells.

[0143] Notably, cell rounding was observed in the immunofluorescence staining images, suggesting a potential loss of cell adhesion and attachment. This observation was further supported by results from the cell adhesion assay (Figure 3J). DLD-1 cells were seeded onto Matrigel-coated wells and treated with various concentrations of NYH102, which is the more potent compound exhibiting anti-metastatic activity. After a 2-hour treatment, the relative number of attached cells was quantified. NYH102 treatment significantly reduced cell adhesion to the Matrigel-coated substratum in a dose-dependent manner, providing additional evidence of its anti-metastatic potential.

[0144] To evaluate the in vivo anti-metastatic potential of NYH102, a tumor metastasis model was established in Balb / cJ mice using the murine colorectal cancer cell line CT26. The cells were injected intravenously, and mice received four doses of either vehicle or 25 mg / kg NYH102 every alternate day via intraperitoneally injection. Mice were monitored and sacrificed upon reaching the predefinedendpoint. Survival data were plotted using a Kaplan-Meier curve, which showed that NYH102 treatment significantly extended the survival of the mice (Figure 3K) and reduced the incidence of lung metastases and associated hemorrhage (Figure 3L) compared to the vehicle-treated controls. These results collectively demonstrate that NYH102 effectively inhibits metastasis in vivo.

[0145] The F-actin cytoskeleton plays a pivotal role in maintaining cell structure and shape, integrating mechanosensory signals, and regulating cell spreading, adhesion, and movement, making it a crucial player in cancer cell EMT and metastasis. Immunofluorescence staining using phalloidin, an anti-F- actin toxin, revealed a significant reduction in F-actin structures following treatment with NYH101 and NYH102 (Figure 4A). This reduction could potentially contribute to the diminished metastatic potential of DLD-1 post-treatment.

[0146] This observation was further confirmed using an invadopodia gelatin degradation assay. Invadopodia, specialized F-actin-rich and cortactin-rich structures found in cancer cells, facilitate cell adhesion and degradative ability by secreting matrix metalloproteinases (MMPs), enabling cancer cells to invade the extracellular matrix (ECM). In this assay, a fluorescent gelatin coating mimicked the ECM. As invadopodia degraded the gelatin, the fluorescent signal was lost, allowing quantification of the area of degradation. The cells were seeded at 30,000, and it was demonstrated that 0.75 pM NYH102 significantly reduced the degradative ability of invadopodia, accompanied by decreased F-actin structures (Figures 4B and 4C).

[0147] YAP1 is a key regulator of F-actin organization, primarily through its role in mechanotransduction and cytoskeletal feedback signaling. The protein levels of YAP1 were assessed in both DLD-1 and HCT1 16 cells treated with NYH101 and NYH102 at various concentrations (Figure 4D), suggesting potential correlations with the loss of F-actin structures.

[0148] In summary, these results collectively indicate that treatment with NYH101 and NYH102 led to reduced cell migration and invasion, likely associated with impaired cytoskeleton structures.

[0149] NYH102 interfered with the cell transcription machinery

[0150] Cellular transcription activity was found to be significantly affected by NYH102 treatment. A reduction in total nucleic acid abundance was observed after 24 hours of treatment with 2.5 pM NYH102, as indicated by SYTO-14 Green staining (Figures 5A and 5B). A reduction in newly transcribed RNA was also observed at earlier timepoints of 1 hour and 3 hours post-treatment with NYH102 at both 2.5 pM and 5 pM (Figures 5C and 5D). These findings suggest that NYH102 treatment impacts mRNA levels during the early stages of the cellular response to the compound.

[0151] A preliminary investigation of the activity of RNA polymerase II (RNAP II), one of the master regulators of transcription, was conducted using Western blot and immunofluorescence staining. While NYH102 treatment led to an overall increase in RNAP II protein levels, Western blot analysis revealed a marked appearance of high molecular weight nonspecific RNAP II within one hour, indicating a possible increase in post-translational modifications (Figure 5E). Immunofluorescence staining confirmed increased RNAP II levels and also revealed altered subcellular localization of RNAP II, with a notable accumulation of RNAP II in the cytoplasm (Figures 5F and 5G). This redistribution suggests that the elevated RNAP II levels may result, at least in part, from a cytoplasmic buildup of transcriptionally inactive RNAP II.

Claims

1. CLAIMS1 . A compound of formula I or a pharmaceutically acceptable salt or solvate thereof,wherein R1to R5are each independently selected from the group consisting of H, halo, CF3, SO2F, and NO2.

2. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and Rs are each independently H or F.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 and R+ are each independently selected from the group consisting of H, F, and CF3.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from the group consisting of H, F, CF3, SO2F, and NO2.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the list consisting of:

6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the list consisting of:

7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

9. Use of the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

10. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer.

11. A method of treating cancer in a subject, wherein the method comprises administering an effective amount of the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, to the subject.

12. The use, the compound for use, or the method of any one of claims 9 to 1 1 , wherein the cancer is one or more selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumors, CNS tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, rectum cancer, colorectal cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia, liver cancer, lung cancer, lung carcinoid tumor, lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor.

13. The use, the compound for use, or the method of claim 12, wherein the cancer is colorectal cancer.

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