Inhibitors of the elongator complex

Abstract

The present invention relates to compounds of formula (I) below, or a pharmaceutically acceptable salt and / or solvate thereof, capable of inhibiting the Elongator complex. The compounds of the invention are for use in the treatment of proliferative diseases and / or viral diseases.

Description

INHIBITORS OF THE ELONGATOR COMPLEXFIELD OF INVENTION

[0001] The present invention relates to compounds of formula (I) capable of inhibiting the Elongator complex. The compounds of the invention are particularly useful in the treatment of proliferative diseases and viral diseases.BACKGROUND OF INVENTION

[0002] Translation dysfunction is associated with more than 100 human diseases. Transfer RNA (tRNA) molecules are essential to decode codons specifying amino acids during protein synthesis. All tRNAs are heavily modified at multiple positions through the addition of chemical groups.

[0003] The wobble uridine (U34) of tRNA molecules is a modified uridine nucleotide localized at position 34 of the tRNAs, which recognizes the third position of numerous A-ending codons. In eukaryotes, wobble uridines are modified by the Elongator complex, a six-subunits (Elpl-6) conserved macromolecular complex, which was first discovered in yeast.

[0004] The Elongator complex is responsible for the modification of the U34 within certain tRNAs, and the formation of cm5U34 (5 ’-carboxymethyluridine) which is the precursor of several derivatives (referred to as xcm5U) including mcm5U34 (5’-methoxycarbonylmethyluridine), ncm5U34 (5 ’-carbamoylmethyluridine), and mcm5s2U34 (5 ’-methoxycarbonylmethyl-2’ -thiouridine). All those modifications are lost when Elongator is absent.

[0005] Among those modifications, the doubly modified uridine mcm5s2U34 is recognized as the most biologically relevant and is found on only three tRNAs (the tRNALysuuu, tRNAGluuuc and tRNAGlnuuo) respectively binding the AAA, GAA andCAA codons. In addition, Ctul was identified as the thiolase responsible for the addition of the s2moiety of the mcm5s2U34.

[0006] The role of these tRNAs modifications is to positively contribute to the kinetics of ribosomal elongation by offsetting the weak A-U interaction. The lack of these tRNAs modifications is not lethal but results in some protein aggregation or proteotoxic stress when there is a high-demand on translation, leading to pleotropic defects. Importantly, only proteins encoded by messenger RNAs (mRNAs) with a codon content skewed for Elongator-dependent decoding are affected.

[0007] While Elongator is dispensable for normal intestinal and breast tissue maintenance, it was reported to be required during WNT-driven intestinal cancer initiation and breast cancer metastasis. In addition, Elongator is crucial for the survival of glycolytic melanoma cells, a form of cancer cells dependent on high level of the Hifla protein. These malignant melanomas are an aggressive form of skin cancer most often linked to a single activating mutation of the BRAF gene (BRAFv600E), on which BRAF inhibitors induce dramatic anti-tumor responses. However, BRAF inhibitors very quickly become inefficient due to resistance, especially resulting from metabolic reprogramming towards glycolysis, which uncouples the tumor growth from BRAF pathway. Depletion of Elongator would resensitize BRAF-mutant tumors to targeted BRAF-therapies by impeding efficient Hifla protein expression, which is needed for glycolysis.

[0008] In addition, the posttranscriptional modification mcm5s2U34 in the tRNALysuuu anticodon domain has been identified as critical for initiation of reverse transcription by human immunodeficiency virus type 1 (HIV-1) (Kleiman, IUBMB Fife 2002; 53(2): 107- 14; Vendeix et al., J Mol Biol, 2012 ;416(4):467-85), suggesting a role for the Elongator complex in HIV-1 infection.

[0009] The Inventors identified chemical compounds, which inhibit the Elongator complex. These compounds are of important therapeutic interest, in particular for the treatment of proliferative diseases, such as various forms of cancer, but also for the treatment of viral diseases, such as HIV-1 infection.SUMMARY

[0010] An object of the present invention is a compound for use in the treatment of a proliferative disease and / or a viral disease; wherein the compound is a compound of Formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein Ar1, X, Y, RAand RBare as defined hereinafter and / or as defined in the claims.

[0011] According to some embodiments, the compound of formula (I) is a compound of Formula (I-a)or a pharmaceutically acceptable salt and / or solvate thereof; wherein X, Y, RA, RBand Rx-R5are as defined hereinafter and / or as defined in the claims.

[0012] In some embodiments, the compound is selected from the compounds of Table 1 herein, and pharmaceutically acceptable salts and / or solvates thereof.

[0013] According to some embodiments, the compound is for use in the treatment of a proliferative disease. In some embodiments, the proliferative disease is cancer, preferablyepithelial cancer, more preferably melanoma, furthermore preferably BRAF-dependent melanoma. According to some embodiments, the viral disease is HIV infection.

[0014] According to some embodiments, the compound is to be administered as sole therapeutic agent. According to other embodiments, the compound is to be administered with at least another therapeutic agent, preferably wherein the at least another therapeutic agent is a BRAF inhibitor or an anti-HIV molecule.

[0015] Another object of the present invention is a pharmaceutical composition for use in the treatment of a proliferative disease and / or a viral disease, wherein the pharmaceutical composition comprises a compound as defined hereinabove and at least one pharmaceutically acceptable carrier.DEFINITIONS

[0016] In the present invention, the following terms have the following meanings:Chemical definitions

[0017] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”. Unless otherwise indicated, the compounds were named using ChemDraw Professional 23.0 (Revvity Signals).

[0018] “Alkoxy” refers to an alkyl-O- group.

[0019] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, furthermore preferably from 1 to 4 carbon atoms. Alkyl groups may be monovalent or polyvalent (z.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). Non-limiting examples ofalkyl groups include methyl, ethyl, / / -propyl, z-propyl, zz-butyl, z-butyl, .s-butyl and / -butyl, pentyl and its isomers (e.g., rz-pentyl, z.so-pcntyl), and hexyl and its isomers (e.g., rz-hexyl, z.so-hcxyl). Particular examples of alkyl groups include methyl, ethyl, zz-propyl, z-propyl, / z-butyl, .s-butyl and / -butyl (including methylene, ethylene, / / -propylene, / / -butylene and n -butylene).

[0020] “Cx-Cy” or “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0021] “Halo” or “halogen” are synonyms and refer to a fluorine, chlorine, bromine or iodine atom.

[0022] “Haloalkyl” refers to an alkyl group wherein at least one hydrogen atom has been replaced by a halogen. Non-limiting examples of haloalkyl groups include monovalent haloalkyls such as, for example, fluoromethyl (CH2F), difluoromethyl (CHF2) and trifluoromethyl (CF3). Particular examples of haloalkyl groups include CHF2 and CF3, preferably CF3.

[0023] “Hydroxy” refers to the -OH group.

[0024] “Nitro” refers to the -NO2 group.

[0025] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound of the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0026] “Pyridinyl” refers to a monovalent derivative of pyridine. Pyridine has the following formula. This definition encompasses a pyridinyl bound to the main structure by any atom from the aromatic ring, thus including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-yl, and pyridin-6-yl (according to the numbering below).

[0027] “Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub-stoichiometric amounts of one or more molecules of one or more solvents, typically the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to a solvate when the solvent is water (H2O).General definitions

[0028] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.

[0029] “Administration", or a variant thereof (e.g., “administering”), means providing a therapeutic agent e.g., a compound of the invention) alone or as part of a pharmaceutically acceptable composition, to a subject, in particular to the patient in whom / which the condition, symptom, or disease is to be treated.

[0030] “BRAF” refers to a serine-threonine kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. BRAF phosphorylates MAP2K1, which activates the MAP kinase signal transduction pathway. Mutations in BRAF gene were found in 60% of melanomas, and at lower frequencies in carcinomas of the colon (15%), lung (3%), breast (3%), and ovary (4%), as well as in glioma (11%). Activating mutations in BRAF gene largely occur in exon 15, which encodes the catalytic domain of BRAF. The most frequent single base change, which consists in a point mutation that involves nucleotide 1799 (i.e., thymine to adenine trans-version at nucleotide 1799, c.l799T>A), results in the substitution of the valine residue at position600 with a glutamic acid residue (V600E mutation) in 80-90% of the cases. This mutation leads to kinase activation and an aberrant activation of the MAPK pathway.

[0031] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence of “comprise” or a variant thereof herein also encompasses narrower expression “substantially consist of’ or “consist essentially of’, further narrower expression “consist of’ and any variants thereof (e.g., “consists of’, “consisting of’), and may be replaced thereby, unless otherwise stated.

[0032] “Human” refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0033] “Patient” refers to a subject who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure, or is monitored for the development of the targeted disease or condition, such as, for example, a proliferative disease or a viral disease.

[0034] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the patient to which / whom it is administered.

[0035] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances suchas phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, poly acrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0036] “Selected from” is used herein according to common patent application drafting terminology, to introduce a list of elements among which one or more item(s) is (are) selected. Any occurrence of “selected from” in the specification may be replaced by “selected from the group comprising or consisting of’ and reciprocally without changing the meaning thereof.

[0037] “Subject” refers to an animal, typically a warm-blooded animal, preferably a mammal. The term “mammal” refers here to any mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a primate, more preferably a human. In some embodiments, the subject is a “patient” as defined herein. In some embodiments, the subject is an adult (for example a subject above the age of 18). In some embodiments, the subject is a child (for example a subject below the age of 18). In some embodiments, the subject is a male. In some embodiments, the subject is a female. In some embodiments, the subject is affected, preferably is diagnosed, with a proliferative disease or a viral disease. In some embodiments, the subject is at risk of developing a proliferative disease or a viral disease. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of proliferative diseases or viral diseases.

[0038] “Therapeutic agent”, “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound of the invention) may be indicated for treating a disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0039] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic, prophylactic or preventative effect in the patient to which / whom it is administered, without causing significant negative or adverse side effects to said patient. A therapeutically effective amount may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the disease, disorder, or condition, for a therapeutic action.

[0040] “Treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder (z.e., a “disease”). Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the condition or disorder is to be prevented. In some embodiments, a subject is successfully “treated” for a disease, disorder, or condition if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound of the invention), the subject shows at least one of the following: relief to some extent of one or more of the symptoms associated with the disease, disorder, or condition to be treated; reduced morbidity and mortality; and improvement in quality-of-life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.DETAILED DESCRIPTION

[0041] The Elongator complex comprises 6 evolutionary conserved subunit proteins referred to as ELP1 to ELP6.

[0042] In the NCBI databases (https: / / www.ncbi.nlm.nih.gov), the reference human ELP1 gene sequence corresponds to NCBI Gene ID 8518 as updated on September 7, 2023. The human ELP1 gene consists of 37 exons localized on chromosome 9q31.3. ELP1 transcript encompasses 5913 nucleotides and encodes a 1332 amino acid protein referenced as NP_003631.2 in the NCBI databases on March 12, 2023.

[0043] Alternatives names for ELP1 include “Elongator Acetyltransferase Complex Subunit 1”, “IKAP”, “Elongator Complex Protein 1”, “IKBKAP”, “TOT1”, “IKI3”, “Inhibitor Of Kappa Light Polypeptide Gene Enhancer In B -Cells, Kinase Complex- Associated Protein”, “IkappaB Kinase Complex-Associated Protein”, “IKK Complex- Associated Protein”, “DYS”, “Dysautonomia (Riley-Day Syndrome, Hereditary Sensory Autonomic Neuropathy Type III)”, “P150”, and “FD”, as non-limiting examples.

[0044] In the NCBI databases, the reference human ELP2 gene sequence corresponds to NCBI Gene ID 55250 as updated on September 7, 2023. The human ELP2 gene consists of 23 exons localized on chromosome 18ql2.2. ELP2 transcript encompasses 8432 nucleotides and encodes a 826 amino acid protein referenced as NP_060725.1 in the NCBI databases on March 15, 2023.

[0045] Alternatives names for ELP2 include “Elongator Acetyltransferase Complex Subunit 2”, “STATIP1”, “StIP”, “Signal Transducer And Activator Of Transcription 3 Interacting Protein 1”, “Elongator Complex Protein 2”, “STAT3 -Interacting Protein 1”, “FLJ10879”, “SHINC-2”, “Elongation Protein 2 Homolog”, “Elongator Protein 2”, “MRT58”, and “StIPl”, as non-limiting examples.

[0046] In the NCBI databases, the reference human ELP3 gene sequence corresponds to NCBI Gene ID 55140 as updated on September 7, 2023. The human ELP3 gene consists of 16 exons localized on chromosome 8p21.1. ELP3 transcript encompasses 3148 nucleotides and encodes a 547 amino acid protein referenced as NP_060561.3 in the NCBI databases on March 11, 2023.

[0047] Alternatives names for ELP3 include “Elongator Acetyltransferase Complex Subunit 3”, “KAT9”, “TRNA Uridine(34) Acetyltransferase”, “Elongator Complex Protein 3”, “FLJ10422”, “Elongation Protein 3 Homolog”, “Protein Lysine Acetyltransferase ELP3”, “EC 2.3.1.48”, “EC 2.3.1.-”, and “HELP3”, as non-limiting examples.

[0048] In the NCBI databases, the reference human ELP4 gene sequence corresponds to NCBI Gene ID 26610 as updated on September 7, 2023. The human ELP4 gene consists of 12 exons localized on chromosome l lpl3. ELP4 transcript encompasses 3148nucleotides and encodes a 424 amino acid protein referenced as NP_061913.3 in the NCBI databases on December 18, 2022.

[0049] Alternatives names for ELP4 include “Elongator Acetyltransferase Complex Subunit 4”, “PAXNEB”, “Cl lorfl9”, “Elongator Complex Protein 4”, “PAX6 Neighbor Gene Protein”, “HELP4”, “Elongation Protein 4 Homolog”, “Chromosome 11 Open Reading Frame 19, “DJ68P15A.1”, “PAX6NEB”, “AN2”, and “AN”, as non-limiting examples.

[0050] In the NCBI databases, the reference human ELP5 gene sequence corresponds to NCBI Gene ID 23587 as updated on September 7, 2023. The human ELP5 gene consists of 10 exons localized on chromosome 17pl3.1. ELP5 transcript encompasses 1491 nucleotides and encodes a 300 amino acid protein referenced as NP_981959.2 in the NCBI databases on December 31, 2022.

[0051] Alternatives names for ELP5 include “Elongator Acetyltransferase Complex Subunit 5”, “DERP6”, “S-Phase 2 Protein”, “C17orf81”, “Dermal Papilla Derived Protein 6”, “Elongator Complex Protein 5”, “Chromosome 17 Open Reading Frame 81”, “Dermal Papilla-Derived Protein 6”, “HSPC002”, “MSTP071”, and “MST071”, as nonlimiting examples.

[0052] In the NCBI databases, the reference human ELP6 gene sequence corresponds to NCBI Gene ID 54859 as updated on September 22, 2023. The human ELP6 gene consists of 10 exons localized on chromosome 3p21.31. ELP6 transcript encompasses 1352 nucleotides and encodes a 266 amino acid protein referenced as NP_001026873.2 in the NCBI databases on December 18, 2022.

[0053] Alternatives names for ELP6 include “Elongator Acetyltransferase Complex Subunit 6”, “C3orf75”, “TMEM103”, “Angiotonin-Transactivated Protein 1”, “Elongator Complex Protein 6”, “Transmembrane Protein 103”, “FLJ20211”, “Elongator Complex Protein 6 Homolog”, “Chromosome 3 Open Reading Frame 75”, “UPF0405 Protein C3orf75”, “Protein TMEM103”, and “ATP1”, as non-limiting examples.

[0054] The present invention relates to a compound of formula (I)whereinAr1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, haloalkyl (e.g., CF3), hydroxy, alkoxy, nitro, or halogen;X represents O, CH2, NH, or S;Y represents S, O, or NH; andRAand RBeach independently represents hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or halogen.

[0055] The present invention preferably relates to a compound of the invention for use in the treatment of a proliferative disease and / or a viral disease.

[0056] In some preferred embodiments, Ar1represents phenyl, wherein the phenyl is optionally substituted by at least one group as defined under formula (I) herein.

[0057] In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, alkoxy, nitro, or halogen. In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, nitro, or halogen. In some particular embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one (C1-C4) alkyl, (C1-C4) alkoxy, nitro, or halogen. In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, alkoxy, nitro, Br, Cl, or I. In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or thepyridinyl is optionally substituted by at least one methyl, methoxy (OCH3), nitro, Br, Cl, or I.

[0058] In some preferred embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, nitro, or halogen. In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one (C1-C4) alkyl, nitro, or halogen. In some preferred embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one methyl, nitro, Br, or Cl.

[0059] In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly zero, one or two group(s) as defined under formula (I) herein, i.e., none, one or two of the substitutable positions of the phenyl or pyridinyl is (are) actually substituted. In some particular embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is not substituted by any groups as defined under formula (I) herein. In some particular embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly one group as defined under formula (I) herein. In some particular embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly two groups as defined under formula (I) herein.

[0060] In some embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly zero, one or two halogen group(s), i.e., none, one or two of the substitutable positions of the phenyl or pyridinyl is (are) actually substituted by halogen. In some particular embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly zero or one halogen group(s). In some preferred embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is substituted by exactly one halogen group. In some other preferred embodiments, Ar1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is not substituted by any halogen group.

[0061] In some embodiments, X represents O or S. In some preferred embodiments, X represents O (i.e., an oxygen atom).

[0062] In some embodiments, Y represents S or O. In some preferred embodiments, Y represents S (z.e., a sulfur atom).

[0063] In some embodiments, RAand RBeach independently represents hydrogen, alkyl, hydroxy, or halogen. In some particular embodiments, RAand RBeach independently represents hydrogen or alkyl. In some embodiments, RAand RBeach independently represents hydrogen or (C1-C4) alkyl. In some embodiments, at least one among RAand RBrepresents hydrogen. In some preferred embodiments, RAand RBeach represents hydrogen.

[0064] In some preferred embodiments, X represents O and Y represents S. In some preferred embodiments, X represents O, Y represents S, and RAand RBeach represents hydrogen.

[0065] In some preferred embodiments, the compound of formula (I) is a compound of Formula (I-a)whereinR1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, nitro, or halogen; andX, Y, RA, and RBare each independently as defined herein under formula (I).

[0066] In some embodiments, R1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, alkoxy, nitro, or halogen. In some embodiments, R1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, nitro, or halogen. In some embodiments, R1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, nitro, or halogen. In some embodiments, R1, R2, R3, R4, and R5each independently represents hydrogen,(C1-C4) alkyl, nitro, or halogen. In some preferred embodiments, R1, R2, R3, R4, and R5each independently represents hydrogen, methyl, nitro, Br, or Cl.

[0067] In some preferred embodiments, R1represents hydrogen, nitro, or Br. In some embodiments, R1represents hydrogen. In some embodiments, R1represents nitro. In some embodiments, R1represents Br.

[0068] In some preferred embodiments, R2represents hydrogen or methyl. In some embodiments, R2represents hydrogen. In some embodiments, R2represents methyl.

[0069] In some preferred embodiments, R3represents hydrogen or Cl. In some embodiments, R3represents hydrogen. In some embodiments, R3represents Cl.

[0070] In some preferred embodiments, R4represents hydrogen.

[0071] In some preferred embodiments, R5represents hydrogen.

[0072] In some further preferred embodiments, R4and R5each represents hydrogen.

[0073] In some embodiments, the phenyl is substituted by exactly zero, one, or two group(s) as defined under formula (I-a) herein, i.e., at least three among R1, R2, R3, R4, and R5represent hydrogen. In some particular embodiments, the phenyl is not substituted by any group as defined under formula (I-a) herein, i.e., each of R1, R2, R3, R4, and R5represents hydrogen. In some particular embodiments, the phenyl is substituted by exactly one group as defined under formula (I-a) herein, i.e., four among R1, R2, R3, R4, and R5represents hydrogen. In some particular embodiments, the phenyl is substituted by exactly two groups as defined under formula (I-a) herein, i.e., three among R1, R2, R3, R4, and R5represents hydrogen.

[0074] In some embodiments, the phenyl is substituted by exactly zero, one or two halogen group(s), i.e., zero, one or two among R1, R2, R3, R4, and R5represent halogen. In some particular embodiments, the phenyl is substituted by exactly zero or one halogen group(s). In some preferred embodiments, the phenyl is substituted by exactly one halogen group. In some other preferred embodiments, the phenyl is not substituted by any halogen group.

[0075] In some preferred embodiments, the compound of formula (I) is a compound ofFormula (I-a-1)(I-a-1) wherein R1, R2, R3, R4, and R5are each independently as defined herein under formula (I- a).

[0076] In some preferred embodiments, the compound is selected from the compounds of Table 1 below, and pharmaceutically acceptable salts and / or solvates thereof.Table 1

[0077] In some preferred embodiments, the compound is selected from (E)-N'-((5-nitrothiophen-2-yl)methylene)-2-phenoxyacetohydrazide (001) and pharmaceutically acceptable salts and / or solvates thereof.

[0078] All references herein to a compound of the invention (e.g., “compound of formula (I)”) include references to salts, solvates, multi component complexes and liquid crystals thereof. All references herein to a compound of the invention include references to polymorphs and crystal habits thereof. All references herein to a compound of the invention include references to isotopically-labelled compounds thereof, including deuterated compounds thereof. All references herein to a compound of the invention include references to stereoisomers thereof. All references herein to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof.

[0079] In particular, the compound according of the invention may be in the form of pharmaceutically acceptable salts. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compoundsare within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also encompasses salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g. , a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0080] In particular, the compounds of the invention may be in the form of pharmaceutically acceptable solvates. According to one embodiment, the compound of the invention is a pharmaceutically acceptable solvate. According to one embodiment, the compound of the invention is a pharmaceutically acceptable salt and solvate.

[0081] In particular, the compounds of the invention may include at least one asymmetric center(s) and thus may exist as different stereoisomeric forms. Accordingly, all references herein to a compound of the invention include all possible stereoisomers and include not only the racemic compounds, but the individual enantiomers and their non-racemic mixtures as well. Non-racemic mixtures may comprise any amounts of each distinct stereoisomer, for example one stereoisomer may be preponderant (e.g., a 90 / 10 or 80 / 20 mixture), or the enantiomeric ratio may be close to a racemic mixture e.g., a 40 / 60 mixture). When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0082] The present invention further relates to a composition comprising, consisting essentially of, or consisting of a compound as described herein.

[0083] As used herein, “consisting essentially of’, with reference to a composition, means that the compound as described herein, is the only one therapeutic agent or agent with a biologic activity within said composition.

[0084] In some embodiments, the composition comprises the compound as described herein as sole active pharmaceutical ingredient.

[0085] In some different embodiments, the composition comprises the compound as described herein and at least another therapeutic agent. In some embodiments, the at least another therapeutic agent is a BRAF inhibitor or an anti-HIV molecule.

[0086] In some embodiments, the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0087] Consequently, another object of the present invention is a pharmaceutical composition comprising, consisting essentially of, or consisting of a compound as described herein, and at least one pharmaceutically acceptable excipient.

[0088] In some embodiments, the pharmaceutical composition comprises the compound as described herein as sole active pharmaceutical ingredient.

[0089] In some different embodiments, the pharmaceutical composition comprises the compound as described herein and at least another therapeutic agent. In some embodiments, the at least another therapeutic agent is a BRAF inhibitor.

[0090] The present invention further relates to a medicament comprising, consisting essentially of, or consisting of a compound as described herein.

[0091] In some embodiments, the medicament comprises the compound as described herein as sole active pharmaceutical ingredient.

[0092] In some different embodiments, the medicament comprises the compound as described herein and at least another therapeutic agent. In some embodiments, the at least another therapeutic agent is a BRAF inhibitor.

[0093] The present invention further relates to a compound, a composition, a pharmaceutical composition, or a medicament as described herein, for use as a medicament.

[0094] The present invention also relates to a compound, a composition, a pharmaceutical composition or a medicament as described herein, for use in the treatment of a proliferative disease and / or a viral disease.

[0095] The present invention also relates to a compound, a composition, a pharmaceutical composition or a medicament as described herein, for treating or for use for treating a proliferative disease and / or a viral disease in a subject in need thereof.

[0096] The present invention further relates to the use of a compound, a composition, a pharmaceutical composition or a medicament as described herein, in the manufacture of a medicament for treating or for the treatment of a proliferative disease and / or a viral disease in a subject in need thereof.

[0097] The present invention also relates to the use of a compound, a composition, a pharmaceutical composition or a medicament as described herein, for treating or for the treatment of a proliferative disease and / or a viral disease in a subject in need thereof.

[0098] The present invention further relates to a method for treating a proliferative disease and / or a viral disease in a subject in need thereof, comprising or consisting of administering a compound, a composition, a pharmaceutical composition or a medicament as described herein, to the subject.

[0099] As used herein, “proliferative disease” refers to a tumor disease (including benign or cancerous) and / or any metastasis, wherever the tumor or the metastasis is located. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is a non-cancerous disease. In some embodiments, the proliferative disease is a benign or malignant tumor.

[0100] As used herein, the term “cancer” has its general meaning in the art and in particular refers to a disease caused by an uncontrolled division of abnormal cells. The term “cancer” encompasses solid tumors and blood cancers, and encompasses both primary and metastatic cancers.

[0101] Examples of cancers include, but are not limited to, cancer from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, pancreatic, skin, stomach, testis, tongue, or uterus.

[0102] In some embodiments, said cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, bladder cancer, bone cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, hepatocellular cancer, kidney cancer, intraocular melanoma, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, neuroblastoma, non- small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, retinoblastoma, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, and testicular cancer.

[0103] In some embodiments, said cancer is selected from intestinal cancer, breast cancer, and melanoma.

[0104] In some embodiments, said cancer is selected from WNT-driven intestinal cancer, breast cancer metastasis, and BRAE-mutated melanoma.

[0105] In some embodiments, said cancer is an epithelial cancer. In some embodiments, said cancer is a melanoma. In some embodiments, said cancer is a BRAE-dependent melanoma. In some embodiments, said cancer is a BRAE-mutated melanoma. In some embodiments, said cancer is a BRAF-mutated melanoma with a BRAFv600Emutation.

[0106] As used herein, “viral disease” refers to the invasion of a subject’s body by pathogenic viruses and infectious virus particles. Seven categories of viruses have beenidentified: double- stranded DNA viruses, single-stranded DNA viruses, positive singlestranded RNA viruses, negative single- stranded RNA viruses, double-stranded RNA viruses, reverse transcribing viruses, and viruses that consist of gapped DNA genomes.

[0107] In some embodiments, the viral disease is a retroviral infection. In some embodiments, the viral disease is induced by a retrovirus.

[0108] In some embodiments, the viral disease is HIV infection. In some embodiments, the viral disease is HIV-1 infection. In some embodiments, the viral disease is induced by HIV. In some embodiments, the viral disease is induced by HIV-1.

[0109] For use in administration to a subject, the compound, composition, pharmaceutical composition or medicament as described herein, will be formulated.

[0110] In some embodiments, the compound, composition, pharmaceutical composition or medicament is administered parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir.

[0111] In some embodiments, the compound, composition, pharmaceutical composition or medicament is administered by injection, including, without limitation, subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intra-stemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0112] Examples of forms adapted for injection include, but are not limited to, solutions, such as, for example, sterile aqueous solutions, gels, dispersions, emulsions, suspensions, solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use, such as, for example, powder, liposomal forms and the like.

[0113] In some embodiments, the compound, composition, pharmaceutical composition or medicament is to be administered to the subject in need thereof in a therapeutically effective amount.

[0114] It will be however understood that the total daily usage of the compound, composition, pharmaceutical composition or medicament as described herein will be decided by the attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the compound employed; the age, body weight, general health, gender and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific therapeutic agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific therapeutic agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total dose required for each treatment may be administered by multiple doses or in a single dose.

[0115] In some embodiments, the dosage of the compound will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing from about 1.0 to 1000 milligrams of the active ingredient, particularly about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, gender, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0116] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is to be administered as sole therapeutic agent.

[0117] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is to be administered as monotherapy.

[0118] In some embodiments, the subject receiving the compound, composition, pharmaceutical composition or medicament as described herein, does not receive any other therapeutic agent in combination with the compound, composition, pharmaceutical composition or medicament as described herein.

[0119] In some embodiments, the subject receiving the compound, composition, pharmaceutical composition or medicament as described herein, does not receive any other therapeutic agent before, concomitantly with, or after receiving the compound, composition, pharmaceutical composition or medicament as described herein.

[0120] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is not to be administered simultaneously, separately or sequentially with another therapeutic agent.

[0121] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is to be administered with at least another therapeutic agent.

[0122] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is to be administered before, concomitantly with, or after at least another therapeutic agent.

[0123] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, is to be administered simultaneously, separately or sequentially with at least another therapeutic agent.

[0124] It will be understood by the one skilled in the art that the co-administration of the compound, composition, pharmaceutical composition or medicament as described herein,with a particular therapeutic agent, which may be chosen among those recited herein but without being limited thereto, will depend on the disease or condition to be treated.

[0125] Some examples of therapeutic agents suitable for co-administration with the compound, composition, pharmaceutical composition or medicament as described herein, include, without limitation, BRAF inhibitors, and anti-HIV molecules.

[0126] In some embodiments, the at least another therapeutic agent is a BRAF inhibitor.

[0127] Examples of BRAF inhibitors include, without limitation, vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), and encorafenib (Braftovi®). Thus, in some embodiments, the BRAF inhibitor is selected from vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), and encorafenib (Braftovi®). In some embodiments, the BRAF inhibitor is vemurafenib.

[0128] In some embodiments, the at least another therapeutic agent is an anti-HIV molecule.

[0129] Examples of anti-HIV molecules include, without limitation, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) such as abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and zidovudine; Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) such as doravirine, efavirenz, etravirine, nevirapine, and rilpivirine; Protease Inhibitors (Pls) such as atazanavir, darunavir, fosamprenavir, ritonavir, and tipranavir; Fusion Inhibitors such as enfuvirtide; CCR5 Antagonists such as maraviroc; Integrase Strand Transfer Inhibitor (INSTIs) such as cabotegravir, dolutegravir, and raltegravir; Attachment Inhibitors such as fostemsavir; Post- Attachment Inhibitors such as ibalizumab-uiyk; Capsid Inhibitors such as lenacapavir; and Pharmacokinetic Enhancers such as cobicistat. Thus, in some embodiments, the anti-HIV molecule is selected from Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (Pls), Fusion Inhibitors, CCR5 Antagonists, Integrase Strand Transfer Inhibitor (INSTIs), Attachment Inhibitors, PostAttachment Inhibitors, Capsid Inhibitors, and Pharmacokinetic Enhancers.

[0130] In some embodiments, the anti-HIV molecule is selected from abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, zidovudine, doravirine, efavirenz, etravirine, nevirapine, rilpivirine, atazanavir, darunavir, fosamprenavir, ritonavir, tipranavir, enfuvirtide, maraviroc, cabotegravir, dolutegravir, raltegravir, fostemsavir, ibalizumab-uiyk, lenacapavir, cobicistat, and combinations thereof.

[0131] In some embodiments, the anti-HIV molecule is a combination of anti-HIV molecules. In some embodiments, the combination of anti-HIV molecules is selected from the combination of abacavir and lamivudine; the combination of abacavir, dolutegravir, and lamivudine; the combination of abacavir, lamivudine, and zidovudine; the combination of atazanavir and cobicistat; the combination of bictegravir, emtricitabine, and tenofovir alafenamide; the combination of cabotegravir and rilpivirine; the combination of darunavir and cobicistat; the combination of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide; the combination of dolutegravir and lamivudine; the combination of dolutegravir and rilpivirine; the combination of doravirine, lamivudine, and tenofovir disoproxil fumarate; the combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate; the combination of efavirenz, lamivudine, and tenofovir disoproxil fumarate; the combination of efavirenz, lamivudine, and tenofovir disoproxil fumarate; the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; the combination of emtricitabine, rilpivirine, and tenofovir alafenamide; the combination of emtricitabine, rilpivirine, and tenofovir disoproxil fumarate; the combination of emtricitabine and tenofovir alafenamide; the combination of emtricitabine and tenofovir disoproxil fumarate; the combination of lamivudine and tenofovir disoproxil fumarate; the combination of lamivudine and zidovudine; and the combination of lopinavir and ritonavir.

[0132] Other therapeutic drugs suitable for co-administration with the compound, composition, pharmaceutical composition or medicament as described herein, include anti-cancer drugs. For instance, the therapeutic drug suitable for co-administration may be a cytotoxin, a chemotherapeutic agent, a lytic peptide or a radioisotope.

[0133] Examples of cytotoxins include, without limitation, radionuclides (e.g.,35S,14C,32P,125I,131I,90Y,89Zr,2O1T1,186Re,188Re,57Cu,213Bi, and211At), conjugated radionuclides, and chemotherapeutic agents. Further examples of cytotoxins include, but are not limited to, antimetabolites (e.g., 5-fluorouricil (5-FU), methotrexate (MTX), fludarabine, etc.), anti-microtubule agents (e.g., vincristine, vinblastine, colchicine, taxanes (such as paclitaxel and docetaxel), etc.), alkylating agents (e.g., cyclophasphamide, melphalan, bischloroethylnitrosurea (BCNU), etc.), platinum agents (e.g., cisplatin (also termed cDDP), carboplatin, oxaliplatin, JM-216, CI-973, etc.), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), antibiotic agents (e.g., mitomycin- C), topoisomerase inhibitors (e.g., etoposide, tenoposide, and camptothecins), or other cytotoxic agents such as ricin, diptheria toxin (DT), Pseudomonas exotoxin (PE) A, PE40, abrin, saporin, pokeweed viral protein, ethidium bromide, glucocorticoid, anthrax toxin and others.

[0134] Examples of chemotherapeutic agents include, without limitation, platinum coordination compounds (such as, e.g., cisplatin, carboplatin or oxaliplatin); taxane compounds (such as, e.g., paclitaxel or docetaxel); topoisomerase I inhibitors (such as, e.g., irinotecan or topotecan); topoisomerase II inhibitors (such as, e.g., etoposide or teniposide); vinca alkaloids (such as, e.g., vinblastine, vincristine or vinorelbine); antitumor nucleoside derivatives (such as, e.g., 5-fluorouracil, gemcitabine or capecitabine); alkylating agents (such as, e.g., nitrogen mustard or nitrosourea, cyclophosphamide, chlorambucil, carmustine or lomustine); anti-tumor anthracycline derivatives (such as, e.g., daunorubicin, doxorubicin, idarubicin or mitoxantrone); anti-HER2 antibodies (such as, e.g., trastuzumab); estrogen receptor antagonists or selective estrogen receptor modulators (such as, e.g., tamoxifen, toremifene, droloxifene, faslodex or raloxifene); aromatase inhibitors (such as, e.g., exemestane, anastrozole, letrazole or vorozole); differentiating agents (such as, e.g., retinoids, vitamin D and retinoic acid metabolism blocking agents [RAMBA] such as accutane); DNA methyl transferase inhibitors (such as, e.g., azacytidine); kinase inhibitors (such as, e.g., flavoperidol, imatinib mesylate or gefitinib); famesyltransferase inhibitors; and HD AC inhibitors.

[0135] Examples of lytic peptides include, without limitation, toxins (such as, e.g., Diptheria toxin or Pseudomonas exotoxin).

[0136] Examples of radioisotopes include, without limitation, the radionuclides of technetium (e.g., Tc-99 and Tc-97), potassium (e.g., K-40), rubidium (e.g., Rb-82), iodine (e.g., 1-123, 1-124, 1-125, 1-129, 1-131), cesium (e.g., Cs-135, Cs-137), cobalt (e.g., Co- 60), palladium (e.g., Pd-103, Pd-107), cadmium (e.g., Cd-113), strontium (e.g., Sr-89, Sr- 90), europium (e.g., Eu-55), tin (e.g., Sn-121, Sn-126), phosphorus (e.g., P-32, P-33), thallium (e.g., Tl-201), indium (e.g., In-111), gallium (e.g., Ga-67, Ga-68), yttrium (e.g., Y-90), iridium (e.g., Ir-192), bismuth (e.g., Bi-213), radium (e.g., Ra-223, Ra-225), and ruthenium (e.g., Ru-106).

[0137] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of tumor cells. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of melanoma tumor cells. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of BRAF-dependent melanoma tumor cells.

[0138] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of tumor cells when combined with a BRAF inhibitor. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of melanoma tumor cells when combined with a BRAF inhibitor. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of BRAF-dependent melanoma tumor cells when combined with a BRAF inhibitor.

[0139] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of vemurafenib-resistant tumor cells when combined with a BRAF inhibitor.

[0140] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of tumor cells when combinedwith vemurafenib. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of melanoma tumor cells when combined with vemurafenib. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of BRAF-dependent melanoma tumor cells when combined with vemurafenib.

[0141] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, decreases the viability of vemurafenib-resistant tumor cells when combined with vemurafenib.

[0142] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes tumor cells to a BRAF inhibitor. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes melanoma tumor cells to a BRAF inhibitor. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes BRAF-dependent melanoma tumor cells to a BRAF inhibitor.

[0143] In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes tumor cells to vemurafenib. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes melanoma tumor cells to vemurafenib. In some embodiments, the compound, composition, pharmaceutical composition or medicament as described herein, resensitizes BRAF-dependent melanoma tumor cells to vemurafenib.

[0144] Therefore, the present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a BRAF-dependent proliferative disease proliferative disease. The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a vemurafenib-resistant proliferative disease. The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a BRAF-dependent cancer or tumor. The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a vemurafenib-resistant cancer or tumor.

[0145] In certain embodiments, the compound, composition, pharmaceutical composition or medicament as described herein is for use in the treatment of a vemurafenib-resistant proliferative disease and wherein vemurafenib is co-administered with the compound, composition, pharmaceutical composition or medicament as described herein. In certain embodiments, the compound, composition, pharmaceutical composition or medicament as described herein is for use in the treatment of a vemurafenib-resistant cancer or tumor and wherein vemurafenib is co-administered with the compound, composition, pharmaceutical composition or medicament as described herein.

[0146] The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a proliferative disease, preferably cancer, in a population of patients or subjects having BRAF- dependent proliferative disease, preferably BRAF-dependent cancer. The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a proliferative disease, preferably cancer, in a population of patients or subjects having vemurafenib-resistant proliferative disease, preferably vemurafenib-resistant cancer.

[0147] The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a proliferative disease, preferably cancer, in a population of patients or subjects having BRAF- dependent tumor cells. The present invention also relates to the compound, composition, pharmaceutical composition or medicament as described herein for use in the treatment of a proliferative disease, preferably cancer, in a population of patients or subjects having vemurafenib-resistant tumor cells.

[0148] The present invention also relates to a method of treating a proliferative disease, preferably cancer, in a population of patients or subjects having BRAF-dependent canceror tumor cells, comprising administering to the patients or subjects a therapeutically effective dose of the compound, composition, pharmaceutical composition or medicament as described herein, and optionally a BRAF inhibitor. The present invention also relates to a method of treating a proliferative disease, preferably cancer, in a population of patients or subjects having vemurafenib-resistant cancer or tumor cells, comprising administering to the patients or subjects a therapeutically effective dose of the compound, composition, pharmaceutical composition or medicament as described herein, and optionally vemurafenib.BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 is a histogram showing in vitro cleavage of tRNAGLUuuc by y-toxin. Yeast cells of ade2-l SUP4 strain were treated for 10 hours with 1 pM of compound 001 (WT+I), or left untreated (WT). In addition, yeast cells of an elp3 deletion mutant (elp3A) were grown. At the end of culture small RNAs were extracted, treated with GST- Zymocin, resolved on a polyacrylamide gel, and probed by Northern blotting using a tRNAGLUuuc labeled antisense probe. ImageQuant was used on Northern Blot images to generate raw / volume data. Proportion of cleaved tRNA was calculated using the formula: raw of cleaved tRNA / (raw of cleaved tRNA + raw of full-length tRNA). Percentage of cleaved tRNA is represented. n=3 independent experiments, data presented as mean ± s.d. (* p<0.05, ** p <0.005 by two-way ANOVA test and Dunnett’s test).

[0150] Figure 2 is a graph showing Elongator’s role in the addition of xcm5-derived modifications on U34. Yeast cells of ade2-l SUP4 strain were treated for 12 hours with 20 pM of compound 001, or left untreated (0 pM). Small RNAs were extracted from cultured yeasts and analyzed by mass spectrometry (LC-MS). Fold change of mcm5U, mcm5s2U, and s2U modifications in budding yeast is represented (** p <0.01 by two-way ANOVA test).

[0151] Figure 3 is a graph showing Elongator’s role in the addition of xcm5-derived modifications on U34. HEK293 cells were treated for 12 hours with 10 pM or 100 pM of compound 001, or left untreated (0 pM). Small RNAs were extracted from the culturedcells and analyzed by mass spectrometry (LC-MS). Fold change of mcm5U, mcm5s2U, and s2U modifications in HEK293 cells is represented (*p<0.05, ** p<0.01, ** p<0.001 by two-way ANOVA test).

[0152] Figure 4 is a histogram showing the impact of compound 001 on the viability of melanoma cell lines. BRAFv600Emelanoma cells (A375 and SK-Mel-28) and BRAFWTmelanoma cells (17T and Sk- Mel-2) were cultured for 72 hours with 12,5 pM of compound 001. At the end of culture, a colorimetric viability assay (MTT assay) was conducted and absorbance was measured at 570 nm. Cell viability was calculated using the following formula: Absorbance of treated cells / Absorbance of untreated cells x 100. Cell viability as a percentage of control is represented. N=3 independent experiments, data presented as mean ± s.d. (*** p<0,001 by one-way ANOVA test).

[0153] Figures 5A-D are a combination of graphs showing the effect of compound 001, Vemurafenib, or compound 001 + vemurafenib on the viability of melanoma cell lines. BRAFV600Emelanoma cells (A375 and SK-Mel-28) and BRAFv600Emelanoma cells resistant to vemurafenib (A375R and SK-Mel-28R) were either (i) cultured for 72 hours with compound 001 (50 pM, 25 pM, 12.5 pM, 6.25 pM, 3.1 pM, 1.56 pM, 0.78 pM, 0.39 pM, or 0.19 pM), (ii) cultured for 72 hours with vemurafenib (20 pM, 10 pM, 5 pM, 2.5 pM, 1.25 pM, 0.625 pM, 0.3125 pM, 0.156 pM , or 0.078 pM), or (iii) cultured for 24 hours with 12,5 pM of compound 001, and then for 48 hours with vemurafenib (20 pM, 10 pM, 5 pM, 2.5 pM, 1.25 pM, 0.625 pM, 0.3125 pM, 0.156 pM, or 0.078 pM). At the end of culture, a colorimetric viability assay (MTT assay) was conducted and absorbance was measured at 570 nm. Cell viability was calculated using the following formula: Absorbance of treated cells / Absorbance of untreated cells x 100. Cell viability as a percentage of control is represented. Data presented as mean ± s.d.Figure 5A represents cell viability of A375R cells.Figure 5B represents cells viability of A375 cells.Figure 5C represents cell viability of SK-Mel-28R cells.Figure 5D represents cells viability of SK-Mel-28 cells.

[0154] Figures 6A-B are photographs showing the growth of ade2-l SUP4 yeasts on a medium supplemented with adenine (SD + CSM - Figure 6A) or an adenine-free medium(SD + CSM - ADE - Figure 6B), in the presence of compound 001, compound 002, compound 003, or compound 004 applied on a round white filter, as indicated.EXAMPLES

[0155] The present invention is further illustrated by the following examples.

[0156] The compounds 001-004 used in the present invention are commercially available (ChemB ridge Diverset library). They were purchased from ChemB ridge Corp. 11199 Sorrento Valley Road, San Diego, California 92121, United States (https : / / chembridge. com / ) .Example 1:Materials and MethodsYeast strain

[0157] An ade2-l SUP4 yeast strain was employed. Ade2 encodes an enzyme necessary for adenine biosynthesis. The ade2-l point mutation replaces GAA codons with UAA codons (i.e., ochre stop codon), resulting in a truncated inactive enzyme. This does not affect growth as long as adenine is supplemented to the medium. The extragenic SUP4 mutation restores adenine prototrophy. SUP4 is a mutated version of tRNATyrGUA, carrying a G to U substitution (i.e., tRNATyruuA) rendering its anticodon complementary to the UAA ochre stop codon. Elongator-dependent modification of the U34 position in SUP4 to mcm5U is crucial for the suppressive action of SUP4.Yeast culture

[0158] ade2-l yeast strains were cultured overnight at 32°C in SD Glucose supplemented with the complete mixture (FORMEDIUM, DCS0019). Subsequentgrowth was observed in both this medium and SD Glucose supplemented with Complete Supplement Mixture (CSM) drop-out adenine (FORMEDIUM, DCS0041).Yeast growth assay - overcoat assay

[0159] Yeasts were cultured in 10 ml of medium at 32°C overnight for pre-culture. Twelve microliters of pre-cultures were added to 4 ml of 1% agar medium. 2 ml were added to a petri dish (94x16) with the same medium. DMSO (2 pl) or 5 mM of compound 001, compound 002, compound 003, or compound 004 (2 pl) were added to a 6 mm diameter pellet of Whatman paper. The pellets were placed on the overcoat, and plates were incubated at 32°C.RNA extraction and tRNA purification

[0160] Yeasts were cultured in targeted medium and incubated at 32°C with treatment. 50 ml (ODeooof 0.5) was pelleted by centrifugation at 4000rpm for 4min at 4°C, washed with 1ml of DEPC-treated water and centrifugated at 12000 rpm for Imin. Cell pellets were frozen at -80°C. Cells were resuspended in 750 pl of TES buffer (500 pl Tris HCL IM pH7.4, 1 ml EDTA 0.5M pH8, 2.5 ml SDS 10%, and 46 ml of DEPC-treated water) and 750 pl of phenol-chloroform (5:1). Cells were shaken for 30s and incubated at 65°C for 1 hour (with shaking intervals at 1300 rpm every 10 minutes) before being placed on ice for 1 minute. RNA-containing aqueous phase (-700 pl) was separated from the phenolic phase by centrifugation at 14,000 rpm for 15min at 4°C, and re-extracted with an equivalent volume of phenol-chloroform-isoamyl alcohol at 14,000 rpm for 5 minutes at 4°C. Aqueous phase (-650 pl) was again re-extracted with 650 pl chloroform-isoamyl alcohol at 14,000 rpm for 5 min at 4°C. 500 pl of RNA were precipitated at -80°C for 30 min with 1.5 ml of cold ethanol and 50 pl of 3M NaAc buffer solution. RNA was harvested by centrifugation at 14,000 rpm for 10 minutes at 4°C and washed with 500 pl of 70% ethanol (stored at 4°C) before drying at room temperature for 10 min. RNA pellets were dissolved in DEPC-treated water and quantified with Nanodrop. RNA samples were stored at -80°C.

[0161] This protocol yields total RNA, but for enrichment in small RNAs (<200nt), the pellets were resuspended in TES buffer and phenol: chloroform (5:1, v / v) and incubatedfor 1 hour at 37 °C. The enrichment in small RNAs was used to obtain RNA extract for Northern Blot and before small RNA purification used in mass spectrometry.

[0162] Two kits were used for small RNA purification. The RNeasy kit (QIAGEN, #74104) was employed for extracting large RNAs (>200 nucleotides), excluding smaller RNAs (<200 nucleotides) during the column purification process. The excluded small RNAs were subsequently recovered and processed using the second kit, miRNeasy Serum / Plasma (QIAGEN, #217184).Northern Blot

[0163] Small RNAs were isolated from a growing culture of ade2-l SUP4 strain treated with or without compound 001 (20 pM during lOhours) and ade2-l SUP4 elp3 \ strain, and used for in vitro Zymocin treatment.

[0164] 3 pg of small RNAs was mixed with purified y-toxin-GST protein in a specific buffer 10X (composed of 100 pl of formamide, 1 pl of EDTA pH8 and O.lpl of 2% bromophenol blue) and 1 mM dithiothreitol (pH 7.5). Samples were denaturized 2 minutes at 95°C and were separated on 9.6% polyacrylamide urea gel (2.5 ml lOx TBE- Tris Borate EDTA buffer, 10.5 g urea, 6 ml acrylamide 40%, 8.2 mL of DEPC-treated water, 25 pl of TEMED and 125 pL of 10% APS) with a run of l-2h at 25mA (600V) in lx TBE. Samples were transferred on Amersham Hybond-xL membrane (RPN203S GE Healthcare) with semi-dry transfer (Owl HEP-1 ThermoFisher Scientific) for 45 minutes at 400mA (6V) and the membrane was crosslinked at 80°C for 2h or Imin with UV.

[0165] Oligonucleotide used to detect tRNA was 5’-CTCCGCTACGGGGAGTCGAAC-3’ (SEQ ID NO: 1) and was labelled using gamma 32P ATP (Perkin Elmer, NEG002A250UC lOmCi / mL) and polynucleotide kinase (PROMEGA, M410A). The radioactive probe was purified using the Illustra Probequant kit (GE28-9034-08 GE Healthcare) following manufacturer’s instructions. The crosslinked membrane was incubated with the radioactive probe overnight at 42°C. Three washes followed the incubation: 15 minutes with 2x SSC (SIGMA, S6639) / 0.1% SDS (Bio-Rad, 1610418), and twice 15 minutes with O.lx SSC / 0.1% SDS. The membrane was dried, exposed to storage phosphor screens (Cytiva, 28956475), andrevealed with a Typhoon scanner (Amersham). Northern blots were visualized and quantified by Phosphor-Imager analysis.Purification of the GST-Zymocin fusion protein

[0166] A total volume of 400 ml of LB medium containing ampicillin was inoculated with E. coli strain BL21 carrying the vector pGEX-y-toxin-GST and grown to ODeoo 0.665 at 37°C. 4 ml of IPTG lOOrnM was added. Culture was incubated 2h at 37°C and centrifugated lOmin at 4500rpm. 20ml of PBS IX was added to the pellet before sonication (5x10s with pause of 2min on ice) and centrifugation at 8000rpm for lOmin at 4°C. The GST proteins (in supernatant) were purified using Glutathione-Sepharose 4B according to manufacturer’s instructions (GE Healthcare Bulk GST Purification module). The purified proteins were fractionated and the collected fractions were monitored using a Bradford assay.Mass spectrometry

[0167] To facilitate the analysis of tRNA samples, 5 pg of each was subjected to hydrolysis in a 40 pL digestion cocktail. The digestion process occurred at 37 °C for 6 hours. For LC-MS analysis, RNA modification HPLC retention times were validated using synthetic standards on a Waters BEH Cl 8 column (50 x 2.1 mm, 1.7 pm) for HEK293 analysis and on a Thermo Hypersil Gold aQ C18 column (100 x 2.1 mm, 1.9 pm) for yeast analysis, coupled to an Agilent 1290 HPLC system and an Agilent 6495 triple-quad mass spectrometer.Human cell culture

[0168] The human melanoma cell line 17T was cultured in RPMI media supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin. The human melanoma cell lines A375, A375R, SK-Mel-28, SK-Mel-28R, SK-Mel-2 and the human embryonic kidney cell line HEK293 were cultured in DMEM media supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. Cells were maintained at 37 °C in a humidified atmosphere of 5% CO2.RNA extraction of HEK293 treated with Elongator inhibitor

[0169] HEK293 cells were seeded into a 12-well plate in complete medium. The cells were treated with various concentrations of compound 001 (0, 10, 100 pM) for 12 hours before being harvested. The culture medium was aspirated, and 500 pl of Ribozol RNA Extraction Reagent (VWR, N580) was added. The cells were then transferred to tubes. 100 pl of chloroform was added, and the samples were vortexed for 15s until an emulsion was formed. Subsequently, the mixture was centrifuged at 12,000g for 10 min at 4°C. The upper phase was carefully transferred to new tubes. Then, 250 pl of isopropanol was added, the tubes were vortexed, and centrifuged at 12,000g for 10 min at 4°C. After removing the supernatant, the pellet was washed with 500 pl of 75% ethanol and centrifuged at 7,500 g for 5 min at 4 °C. Once the supernatant was removed, the pellet was air-dried for 15 min at room temperature and then resuspended in 30 pl of RNase-free water. Samples were purified with PureLink miRNA Isolation Kit (Invitrogen, K157001) following manufacturer’s instructions.MTT assay

[0170] For the viability assay, 1000 cells per well for A375 and SK-MEL-28 cell lines and 3000 cells per well for Sk-Mel-2 and 17T cell lines were seeded into 96-well plate in complete medium. After 24 hours, cells were treated with 12,5 pM of compound 001.

[0171] For the resistance to vemurafenib assay, 1000 cells per well of A375, A375R, SK-MEL-28, and SK-MEL-28R cells were seeded into 96-well plate in complete medium. After 24 hours, cells were treated with either (i) 50 pM, 25 pM, 12.5 pM, 6.25 pM, 3.1 pM, 1.56 pM, 0.78 pM, 0.39 pM, or 0.19 pM of compound 001 for 72 hours, (ii) 20 pM, 10 pM, 5 pM, 2.5 pM, 1.25 pM, 0.625 pM, 0.3125 pM, 0.156 pM, or 0.078 pM vemurafenib for 72 hours, or (iii) 12,5 pM of compound 001 for 24 hours, then medium was replaced with 20 pM, 10 pM, 5 pM, 2.5 pM, 1.25 pM, 0.625 pM, 0.3125 pM, 0.156 pM, or 0.078 pM vemurafenib for 48 hours.

[0172] After 72 hours treatment, 20pl of 5 mg / ml of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) (Carl Roth, Karlsruhe, Germany) solution was added to each well and incubated for 3 hours. Media with MTT was removed, and cells were solubilized using 150pl of dimethylsulf oxid (DMSO) (Carl Roth, Karlsruhe,Germany). Absorbance was measured at 570 nm on a SpectraMax i3 plate reader (Molecular Devices, San Jose, CA). MTT tetrazolium salt (which is yellow) is reduced in formazan (which is purple). The content of precipitate formed is proportional to the quantity of living cells. The relative quantity of living cells with an active metabolism is measured by spectrophotometry.ResultsCleavage oftRNAGLUuuc by y- toxin

[0173] Zymocin (also known as y-toxin), is a heterotrimeric ribonuclease from the dairy yeast Kluyveromyces lactis that specifically targets and cleaves tRNAs bearing the Elongator dependent mcm5modification, leading to cell death. The toxin has low activity on human cells because they express an endogenous tRNA ligase that counteracts the effect of the nuclease by religating the cleaved tRNAs.

[0174] In order to test the ability of Zymocin to cleave tRNAs purified from yeast cells treated with compound 001, a GST-Zymocin fusion was expressed and purified in Escherichia coli. Small RNAs (<200 nt) were extracted from untreated yeast cells, yeast cells grown in the presence of IpM of compound 001, as well as from isogenic yeast cells deleted for elp3 (i.e., a subunit of Elongator) as a control. After treatment with GST- Zymocin, small RNAs were resolved on a polyacrylamide gel (PAGE) and probed by Northern blotting using a tRNAGluuuc labeled antisense probe, as this tRNA is a target of Elongator. As shown on Figure 1, tRNAs purified from the wild-type yeast strain (WT) exhibited tRNA cleavage by Zymocin. On the opposite, tRNAs purified from the Elongator deficient strain (elp3d) were fully resistant to Zymocin cleavage (Figure 1). Finally, cells treated with compound 001 showed a strong decrease in cleavage (Figure 1). These data suggest that compound 001 interferes with the synthesis of the xcm5U.Elongator ’s role in the addition of xcm5-derived modifications on U34

[0175] The next goal was to directly measure the level of the Elongator-dependent modifications in yeast cells treated with compound 001 using mass spectrometryLC-MS / MS. Yeast cells were grown either untreated or in the presence of 20 pM of compound 001 for 12 hours. As shown on Figure 2, yeast cells treatment with compound 001 resulted in a significant decrease of the level of ncm5and in a unsignificant decrease of mcm5s2modified uridine, as compared to untreated yeast cells. Corroborating these data, the level of s2U increased, as compared to untreated yeast cells (Figure 2), which is likely due to the loss of the Elongator-dependent mcm5moiety in the doubly modified mcm5s2U.

[0176] Then, the effect of compound 001 was tested on HEK293 cells by mass spectrometry LC-MS / MS. HEK293 cells were cultured either untreated, or in the presence of 10 p M or 100 pM of compound 001 for 12 hours. Then, small RNAs (<200nt) were extracted from the cells and a LC-MS / MS was performed. The analyses revealed statistically significant decrease in the level of the ncm5U and mcm5s2U species, and an increase in s2U level (Figure 3). The data are reminiscent of the effect observed in yeast and suggest that compound 001 also affects Elongator activity in human cells.Viability of melanoma cells

[0177] It has been previously demonstrated that the knockdown of ELP3 compromises the viability of human BRAFv600Emelanoma cells, while leaving normal human melanocytes and two unrelated BRAFWTmelanoma cultures unaffected (Rapino el al., Nature 558, 605-609 (2018)). Therefore, two BRAFv600Emelanoma cell lines (A375, SKMEL28) were used in order to determine if compound 001 was able to reproduce this effect, as well as two independent BRAFWTmelanoma cultures (17T, SKMEL2) used as controls. Cells were cultured for 72 hours with 12.5 pM of compound 001. Then, a colorimetric viability assay (MTT test) was conducted on the four treated cell lines. As shown on Figure 4, the viability of BRAFv600Ecell lines (z.e., A375 and SKMEL28 cells) was significantly decreased compared to BRAFWTcell lines (i.e., 17T and SKMEL2 cells) after 72 hours of treatment with compound 001.

[0178] These data demonstrate that treatment of human BRAFv600Emelanoma cells (A375 and SKMEL28) with compound 001 mimics the knockdown of Elongator in terms of the modified uridine levels and its impact on melanoma cell viability.Resistance to Vemurafenib

[0179] Melanoma cell lines A375R and SK-Mel-28R were created from BRAFv600Emelanoma cells (A375 and SK-Mel-28), which were made resistant to vemurafenib (i.e., BRAF inhibitor).

[0180] Cell viability of A375, A375R, SK-Mel-28, and SK-Mel-28R cells was measured after culture in the presence of compound 001 alone, vemurafenib alone, or compound 001 with vemurafenib (Figures 5A-D).

[0181] As shown on Figures 5A-D, none of the cell line viability was affected by the presence of compound 001 alone at low concentrations (0.19 pM, 0.39 pM, 0.78 pM, 1.56 pM). From 3.1 pM of compound 001, a decrease of cell viability can be observed for A375 cells (Figure 5B), SK-Mel-28R cells (Figure 5C), and SK-Mel-28 cells (Figure 5D), while decrease starts from 6,25 pM of compound 001 for A375R cells (Figure 5A).

[0182] Vemurafenib alone induced a dose-dependent decrease of viability on all cell lines (Figures 5A-D), which was even more pronounced on A375 (Figure 5B) and SK- Mel-28 cells (Figure 5D) which are not resistant to vemurafenib.

[0183] The combination of compound 001 with vemurafenib drastically reduced the cell viability of A375R cells (Figure 5A) and SK-Mel-28R cells (Figure 5C), in a dosedependent manner, as compared to A375R cells and SK-Mel-28R cells treated with vemurafenib alone.

[0184] These data show that A375R cells and SK-Mel-28R cells pretreated with compound 001, before treatment with vemurafenib exhibit a reduced cell viability, as compared to A375R cells and SK-Mel-28R cells which were treated with vemurafenib only. Thus, these data demonstrate that compound 001 was able to resensitize resistant cells to vemurafenib treatment.Additional compounds

[0185] Compounds 001, 002, 003, and 004 were applied on a white filter either on an adenine-free medium, or a medium supplemented with adenine, and the growth of ade2-l SUP4 yeasts was tested.

[0186] Compound 002, compound 003, and compound 004, were able to prevent an ade2-l SUP4 strain from growing on a medium without adenine, similarly to compound 001 (Figures 6A-B), as shown by the halo of growth inhibition around the white filter. These results demonstrate that compound 002, compound 003, and compound 004 inhibit Elongator, similarly to compound 001.

Claims

CLAIMS1. Compound for use in the treatment of a proliferative disease and / or a viral disease; wherein the compound is a compound of Formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; whereinAr1represents phenyl or pyridinyl, wherein the phenyl or the pyridinyl is optionally substituted by at least one alkyl, haloalkyl, hydroxy, alkoxy, nitro, or halogen; X represents O, CH2, NH, or S;Y represents S, O, or NH; andRAand RBeach independently represents hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, or halogen.

2. The compound for use according to claim 1, wherein X represents O.

3. The compound for use according to claim 1 or claim 2, wherein Y represents S.

4. The compound for use according to any one of claims 1 to 3, wherein at least one among RAand RBrepresents hydrogen, preferably RAand RBeach represents hydrogen.

5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) is a compound of Formula (I-a)or a pharmaceutically acceptable salt and / or solvate thereof; whereinR1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, nitro, or halogen; andX, Y, RA, and RBare each independently as defined in claim 1.

6. The compound for use according to claim 5, wherein R1, R2, R3, R4, and R5each independently represents hydrogen, alkyl, nitro, or halogen; preferably wherein R1,R2, R3, R4, and R5each independently represents hydrogen, methyl, nitro, Br, or Cl.

7. The compound for use according to claim 5 or claim 6, wherein R4represents hydrogen.

8. The compound for use according to any one of claims 5 to 7, wherein R5represents hydrogen.

9. The compound for use according to claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts and / or solvates thereof.

10. The compound for use according to any one of claims 1 to 9, wherein the compound is for use in the treatment of a proliferative disease.

11. The compound for use according to claim 10, wherein the proliferative disease is cancer, preferably epithelial cancer, more preferably melanoma, furthermore preferably BRAF-dependent melanoma.

12. The compound for use according to any one of claims 1 to 11, wherein the viral disease is HIV infection.

13. The compound for use according to any one of claims 1 to 12, wherein the compound is to be administered as sole therapeutic agent.

14. The compound for use according to any one of claims 1 to 12, wherein the compound is to be administered with at least another therapeutic agent, preferably wherein the at least another therapeutic agent is a BRAF inhibitor or an anti-HIV molecule.

5. Pharmaceutical composition for use in the treatment of a proliferative disease and / or a viral disease, wherein the pharmaceutical composition comprises a compound as defined in any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.

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