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WO2024200612A1 - Inhibiteurs du catabolisme et/ou du transport de l'uridine à usage thérapeutique - Google Patents

Inhibiteurs du catabolisme et/ou du transport de l'uridine à usage thérapeutique Download PDF

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WO2024200612A1
WO2024200612A1 PCT/EP2024/058419 EP2024058419W WO2024200612A1 WO 2024200612 A1 WO2024200612 A1 WO 2024200612A1 EP 2024058419 W EP2024058419 W EP 2024058419W WO 2024200612 A1 WO2024200612 A1 WO 2024200612A1
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cas
methyl
pyrimidin
uridine
butyl
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Alexis JOURDAIN
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Universite de Lausanne
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a screening method for the identification of inhibitors of nucleotide catabolism, such as uridine catabolism, to the inhibitors identified by the screening method and use thereof in oncology, immune modulation and metabolic disorder.
  • Glucose is vital for life, serving both as a source of energy and carbon building block for growth.
  • alternative nutrients are used by cells. It has been recently reported that catabolism of uridine or RNA enables cells to grow in the complete absence of glucose.
  • uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial electron transport chain deficiency
  • the ribose moiety of uridine or RNA can be salvaged to fulfill energy requirements via uridine catabolism pathway defined as: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/2 into uracil and ribose- 1 -phosphate (RIP), (2) the conversion of RIP into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway (non-oxPPP), and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis.
  • uridine catabolism pathway defined as: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/2 into uracil and ribose- 1 -phosphate (RIP), (2) the conversion of RIP into fructose-6-
  • Such catabolism of uridine appears widespread, and its activity can be found in liver, activated macrophages, and certain cancer lineages.
  • An interesting property of such uridine catabolism is that uridine enters downstream of the initial, highly regulated steps of glucose transport and glycolysis.
  • metabolic inhibitors are a new, highly attractive area of research for oncology, immune and metabolic modulation.
  • drugs are approved or in clinical trials (I to III) for multiple types of cancers.
  • Those drugs generally target energy producing pathway such as glycolysis, mitochondrial respiration, glutaminolysis, fatty acid oxidation and more.
  • those drugs may fail due to the metabolic flexibility of cells. Metabolic flexibility is usually defined by the ability that cells have to switch from one energy source to another. For example, the action of an inhibitor of glycolysis may be bypassed by fatty acids oxidation.
  • identifying and drugging alternative pathways for energy production is of high interest for cancer research, but also immune modulation and metabolic syndromes.
  • Nucleotides are abundant in human diet, and every living organism ingested by humans, whether animal- or plant-based, contains DNA and RNA. It has been recently reported that organisms can assimilate and derive energy from nucleotides and nucleic acids, as described above. It has been shown that cells deprived of glucose (or genetically, or chemically, unable to perform glycolysis) can use nucleotides and nucleic acids as energy producing substrates. Thus, nucleotides play a critical role in maintaining cellular function and energy metabolism. Uridine, a pyrimidine nucleotide characterized by its high abundance and solubility is one of the most commonly used nucleotides for energy production.
  • Uridine is mostly present in blood and cerebrospinal fluid, where it contributes to the maintenance of basic cellular functions affected by uridine phosphorylase 1 and 2 (UPP1 and UPP2) enzyme activities, feeding habits, and ATP depletion. Uridine is also highly abundant in organs and in the diet. Uridine metabolism depends mainly on three stages: (1) de novo synthesis, (2) salvage, and (3) catabolism, all of which are tightly relating to glucose homeostasis, and lipid and amino acid metabolism.
  • nucleotides catabolism Due to the important roles of uridine, especially as an alternative energy source, there is a need for efficient and simple methods that can identify inhibitors of nucleotides catabolism, preferably uridine catabolism, and thereby prevent use of nucleotides as energy source by cells.
  • An aspect of the present invention provides a use of an inhibitor for in-vitro inhibiting uridine catabolism and/or for in-vitro inhibiting uridine transport, wherein the inhibitor is selected from the group comprising
  • Mubritinib derivative 2 • (E)-4-((4-(4-(lH-l,2,3-triazol-l-yl)butyl)phenoxy)methyl)-2-((4- methyl)styryl)oxazole, Mubritinib derivative 3
  • Another aspect of the present invention provides an inhibitor of the invention for use in a method for treating a disease associated with uridine catabolism selected from cancer and immune disorders, and wherein the cancer expresses high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • UPP1 Uridine phosphorylase 1
  • UPP2 Uridine phosphorylase 2
  • Figure 1 shows method for identifying inhibitors of uridine catabolism for energy production.
  • a cell line with high ability to grow on uridine is selected.
  • Cells are transferred to glucose-free media.
  • Ill Cells are divided in two, and each half is supplemented with an equal concentration of glucose or of uridine.
  • IV Cells are then plated on multi-well plates, themselves pre-coated with the drug library.
  • V Cells are incubated for a few days.
  • a viability dye such as Prestoblue, is added to each well.
  • the viability of cells is estimated based on the signal of the viability dye in glucose or in uridine.
  • FIG. 2 shows screen results for uridine catabolism inhibitors.
  • UACC-257 cells were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine. Supplemented cells were then plated on 384-well plates pre-coated with compounds from the Prestwick library (Prestwick, 1’280 compounds), a kinase inhibitor library (Sellekchem, 258 compounds), or a nucleoside library (Enamine, 320 compounds) as shown in Figure 2A, or compounds from a chemically diverse collection (7’678 compounds) as shown in Figure 2B. The final concentration of inhibitors is lOpM. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and Z-scores were calculated. Compounds were selected for further investigation based on their Z-scores.
  • Figure 3 shows uridine promotes cell survival and energy metabolism, illustrated here by lactate production, in Primary Peripheral Blood Mononuclear Cells (PBMC).
  • PBMC Primary Peripheral Blood Mononuclear Cells
  • Figure 4 shows validation of the compounds (identified with CAS numbers) in AsPCl pancreatic cancer cells.
  • Cells were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine, and treated with the drugs of interest at a lOpM concentration. After 72h, Prestoblue was added. Relative Prestoblue fluorescence was measured after 2h. Fold change in viability compared to untreated control cells.
  • Figure 5 shows validation of the compounds (identified with CAS numbers) in SW480 colon cancer cells.
  • Cells were diluted in glucose-free media supplemented with 10M glucose or lOmM uridine, and treated with the drugs of interest at a lOpM concentration. After 72h, Prestoblue was added. Relative Prestoblue fluorescence was measured after 2h. Fold change in viability compared to untreated control cells.
  • Figure 6 shows validation of the compounds (identified with CAS numbers) in U937 histiocytic lymphoma monocytic cells.
  • Cells were diluted in glucose-free media supplemented with lOOnM phorbol-12-myristate-13-acetate (PMA) and with 10M glucose or lOmM uridine, and treated with the drugs of interest at a lOpM concentration.
  • PMA phorbol-12-myristate-13-acetate
  • 10M glucose or lOmM uridine 10M glucose or lOmM uridine
  • Relative Prestoblue fluorescence was measured after 2h. Fold change of viability compared to untreated control cells.
  • Figure 7 shows validation of the compounds (identified with CAS numbers) in UACC-257 melanoma cells.
  • Figure 8 shows validation of the compounds (identified with CAS numbers) in an in vitro system containing recombinant human UPP1 enzyme (2ng/pL), phosphate buffer (0.1M), uridine (2mM final) and the drugs of interest at a lOpM concentration.
  • Absorbance at 280nm is proportional to the catabolism of uridine and was measured over Ih. Fold change in activity compared to DMSO.
  • Figure 9 shows validation of Mubritinib derivatives in UACC-257 melanoma cells.
  • Cells were diluted in glucose-free media supplemented with 10M glucose (grey) or lOmM uridine (blue), and treated with the drugs of interest at a lOpM concentration. After 72h, Prestoblue was added. Relative Prestoblue fluorescence was measured after 2h. Fold change in viability compared to untreated control cells.
  • Figure 10 shows a bioinformatic analysis of UPP1 expression levels across 1,479 cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE), corresponding to 33 cancer lineages and 76 sub-lineages. Highlighted in red are cancers with high UPP1 expression, such as pancreatic cancers and melanoma. High UPP1 expression is defined as log2(TPM+l) > 5. “HC + IC” corresponds to “Hepatocellular Carcinoma plus Intrahepatic Cholangiocarcinoma”. “UPS/MFH/HGSCS” corresponds to “Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma.”
  • nucleotides refer to (1) desoxyadenosine, adenosine, thymidine, desoxyuridine, uridine, deoxypseudoruridine, pseudouridine, deoxyguanosine, guanosine, deoxycytidine, cytidine, deoxyinosine and inosine, in non-, mono-, di-, or tri-phosphorylated forms.
  • Non-phosphorylated nucleotides are also called “nucleosides”; (2) nucleotide polymers (nucleic acids in general and in particular DNA and RNA); (3) nucleotide derivative (adenine, guanine, cytosine, uracil, thymine, pseudouracil, hypoxantine, xanthine, ribose- 1 -phosphate, ribose-5-phosphate, phosphoribosylpyrophosphate); (4) dinucleotides such as nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADH nicotinamide adenine dinucleotide
  • NADPH nicotinamide adenine dinucleotide phosphate
  • catabolism refers to the breakdown of complex molecules in living organisms to form simpler ones, in certain cases accompanied by the release of energy. It includes, but is not limited to, the breakdown (catabolism) of nucleotides, such as uridine that typically includes (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/2 into uracil and ribose- 1 -phosphate (RIP); (2) the conversion of RIP into ribose-5-phosphate (R5P) by a phosphoglucomutase; (3) the conversion of R5P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway (non-oxPPP); and (4) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis.
  • nucleotides such as uridine that typically includes (1) the phosphorylytic cleavage of uridine by uridine phosphorylase
  • inhibitor of nucleotide catabolism refers to a compound, a gene or an antibody which, when tested in the screening method of the present invention, prevents or reduces the growth of cells in the presence of a nucleotide, such as uridine, but not in the presence of glucose and that prevents or reduces the growth of cells in comparison with the blank incubation.
  • the terms "subject” and “patient” are well-recognized in the art, and, are used herein to refer to a mammal, and most preferably a human.
  • the subject is a subject in need of treatment and/or a subject having a disease selected from a cancer, immune disorders and metabolic disorders.
  • the term does not denote a particular age or sex. Thus, individuals of all ages, from newborn to adult, whether male or female, are intended to be covered.
  • an "effective amount" of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • An effective amount can be provided in one or more administrations.
  • a "therapeutically effective amount” is at least the minimum concentration required to effect a measurable improvement of a particular disorder (e.g., a cancer, immune disorders and metabolic disorders).
  • a therapeutically effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the inhibitors of the present invention to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the inhibitors of the present invention are outweighed by the therapeutically beneficial effects.
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • the inhibitors of the present invention are used to delay development of a disease or to slow the progression of a disease.
  • the disease is cancer, immune disorder or metabolic disorder. An individual is successfully "treated”, for example, if one or more symptoms associated with a cancer, immune disorder and/or metabolic disorder are mitigated or eliminated.
  • the catabolism of uridine typically includes (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/2 into uracil and ribose- 1 -phosphate (RIP); (2) the conversion of RIP into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway (non-oxPPP); (3) the conversion of R5P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway (non- oxPPP); and (4) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis.
  • RIP uracil and ribose- 1 -phosphate
  • R5P the conversion of R5P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate
  • an aspect of the present invention provides a screening method for identification of inhibitors of nucleotide catabolism, said method comprising the steps of
  • step (ii) incubating the cell line of step (i) on glucose-free media comprising a nucleotide and a test compound;
  • step (iii) incubating the cell line of step (i) on nucleotide-free media comprising glucose and a test compound;
  • step (iv) incubating the cell line of step (i) on glucose-free media comprising the nucleotide without a test compound (blank incubation);
  • step (ii) • reduces the growth of cells in step (ii), but not in step (iii), • reduces the growth of cells in step (ii) comparing to the blank incubation of step
  • step (vii) optionally determining the half maximal inhibitory concentration (IC50) of the compounds selected in step (vi).
  • the nucleotide is selected from the group comprising adenosine, uridine, pseudouridine, guanosine, cytidine and inosine.
  • An embodiment of the screening method of present invention provides a screening method for identification of inhibitors of uridine catabolism, said method comprising the steps of
  • step (ii) incubating the cell line of step (i) on glucose-free media comprising uridine and a test compound;
  • step (iii) incubating the cell line of step (i) on uridine-free media comprising glucose and a test compound;
  • step (iv) incubating the cell line of step (i) on glucose-free media comprising uridine without a test compound (blank incubation);
  • step (ii) • reduces the growth of cells in step (ii) comparing to the blank incubation of step (iv)
  • step (vii) optionally determining the half maximal inhibitory concentration (IC50) of the compounds selected in step (vi).
  • the growth of cells in step (ii) is at least 2-fold less comparing to step (iii) and/or step (iv).
  • step (vii) optionally determining IC50 in step (vii) is carried out
  • IC50 is a concentration of an inhibitor that causes 50% inhibition of the growth of cells.
  • the cell line of step (i) is UACC-257, UACC-57, A2058, SK-MEL5, SK-MEL30, MDA-MB-435S, LOX-IMVI, SH4 melanoma cells, AsPCl pancreatic cancer, SW480 colon cancer, U937 monocytic cells, or any cell line with detectable levels of UPP1 or UPP2 gene expression and/or ability to grow using a nucleotide, such as uridine, as an energy source ; or a cell line engineered to express UPP1 or UPP2; or a cell line with natural or artificial high level expression of the UPP1 or UPP2 gene.
  • a nucleotide such as uridine
  • a cell line engineered to express UPP1 or UPP2 or a cell line with natural or artificial high level expression of the UPP1 or UPP2 gene.
  • the duration of the incubation of steps (ii), (iii), and (iv) is typically 72 hours, in some embodiments the incubation time is 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, or selected within 24 hours to 84 hours, or 48 hours to 84 hours.
  • a suitable glucose-free media comprising uridine is typically glucose-free RPMI (Roswell Park Memorial Institute) medium supplemented with a nucleotide, such as uridine, or glucose-free DMEM (Dulbecco's Modified Eagle's Medium) supplemented with a nucleotide, such as uridine.
  • a glucose-free media supplemented with a nucleotide, such as uridine generally comprise a nucleotide, such as uridine, as a sole source of sugar and compounds which promote the growth and replication of cells.
  • a typical glucose-free culture medium is composed of a complement of amino acids, vitamins, inorganic salts, a nucleotide, such as uridine, and dialyzed serum as a source of growth factors, hormones, and attachment factors.
  • a suitable nucleotide-free media such as uridine-free media, comprising glucose is typically nucleotide free, such as uridine-free, RPMI (Roswell Park Memorial Institute) medium supplemented with glucose or nucleotide-free, such as uridine-free, DMEM (Dulbecco's Modified Eagle's Medium) supplemented with glucose.
  • a nucleotide-free, such as uridine-free, media supplemented with glucose generally comprise glucose as a sole source of sugar and compounds which promote the growth and replication of cells.
  • a typical nucleotide-free, such as uridine-free, culture medium is composed of a complement of amino acids, vitamins, inorganic salts, glucose and dialyzed serum as a source of growth factors, hormones, and attachment factors.
  • incubation of cell lines is typically carried out in an incubator with a tightly regulated temperature and CO2 concentration.
  • Cell lines typically grow at 37°C and 5% CO2 with saturating humidity.
  • measuring the growth of cells in steps (ii), (iii), (iv) and/or (v) is carried out by addition of a cell viability dye, such as Prestoblue.
  • Another aspect of the present invention provides an inhibitor of nucleotide catabolism, such as uridine catabolism, and/or nucleotide transport, such as uridine transport, identified by the screening method of the present invention.
  • the preferred embodiments of the present invention provide an inhibitor of uridine catabolism and/or uridine transport, identified by the screening method of the present invention.
  • Another aspect of the present invention provides an inhibitor of nucleotide transport, identified by the screening method of the present invention.
  • the preferred embodiments of the present invention provide an inhibitor of uridine transport, identified by the screening method of the present invention.
  • Another aspect of the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • Mubritinib derivative 2 • (£)-4-((4-(4-(lH-l,2,3-triazol-l-yl)butyl)phenoxy)methyl)-2-((4- methyl)styryl)oxazole, Mubritinib derivative 3
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or in-vitro inhibiting uridine transport.
  • the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • Mubritinib derivative 2 • (E)-4-((4-(4-(lH-l,2,3-triazol-l-yl)butyl)phenoxy)methyl)-2-((4- methyl)styryl)oxazole, Mubritinib derivative 3
  • N-[l-(2,3-Dihydro-l,4-benzodioxin-6-yl)-2-methylpropyl]thieno[3,2-d]pyrimidin-4- amine (CAS: 930038-39-4) that is used for inhibiting nucleotide catabolism, preferably uridine catabolism and/or for inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or for in-vitro inhibiting uridine transport.
  • the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or for in-vitro inhibiting uridine transport.
  • the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or in-vitro inhibiting uridine transport.
  • the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • N-[l-(2,3-Dihydro-l,4-benzodioxin-6-yl)-2-methylpropyl]thieno[3,2-d]pyrimidin-4- amine (CAS: 930038-39-4) that is used for inhibiting nucleotide catabolism, preferably uridine catabolism and/or for inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or for in-vitro inhibiting uridine transport.
  • the present invention provides an inhibitor, that can be identified by the screening method of the present invention, selected from the group comprising
  • Mubritinib derivative 7 that is used for inhibiting nucleotide catabolism, preferably uridine catabolism and/or for inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting nucleotide catabolism, preferably uridine catabolism and/or for in-vitro inhibiting nucleotide transport, preferably uridine transport.
  • the inhibitors are used for in-vitro inhibiting uridine catabolism and/or for in-vitro inhibiting uridine transport.
  • Such in-vitro inhibiting is helpful in setting-up assays, screening methods or evaluating the inhibition of different inhibitors. Further, such an in-vitro inhibiting involves an in-vitro method comprising a cell incubation.
  • Another aspect of the present invention provides an inhibitor of nucleotide catabolism, preferably uridine catabolism, of the present invention for use in a method for treating a disease associated with nucleotide catabolism, preferably uridine catabolism.
  • the disease associated with nucleotide catabolism, preferably uridine catabolism is selected from the group comprising cancer, immune disorders and metabolic disorders, wherein the cancer expresses high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2). See for example Figure 10.
  • the disease associated with uridine catabolism is selected from cancer and immune disorders, wherein the cancer expresses high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • the cancer is selected from the group comprising pancreatic ductal adenocarcinoma (PDA), melanoma and colon cancer.
  • the disease associated with uridine catabolism is cancer expressing high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • the cancer is selected from the group comprising pancreatic ductal adenocarcinoma (PDA), melanoma and colon cancer.
  • high level As herein used, “high level”, “high level expression” or “high UPP1 expression” is defined as log2(TPM+l) > 5, wherein TPM are “transcripts per million”. TPM are a standard way to measure gene expression, and are calculated as follows:
  • RPK values in a sample are counted up, and divided by 1,000,000. This number is the “per million” scaling factor.
  • the present invention provides a method for treating a disease associated with nucleotide catabolism, preferably uridine catabolism, in a subject, the method comprising administering an inhibitor of the nucleotide catabolism, preferably uridine catabolism, of the present invention to the subject.
  • the disease associated with nucleotide catabolism, preferably uridine catabolism is selected from the group comprising cancer, immune disorders and metabolic disorders.
  • the disease associated with uridine catabolism is selected from cancer and immune disorders.
  • the inhibitor of nucleotide catabolism, preferably uridine catabolism is administered in a therapeutically effective amount.
  • the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention are used in methods for treating a cancer either alone, as monotherapy, or in combination with other types of therapies such as immunotherapy, radiotherapy and/or chemotherapy.
  • the method for treating a cancer further comprises administering to a subject one or more cancer immunotherapeutic agents selected from the group comprising an immune checkpoint inhibitor, a TCR-T cells, and a CAR-T cells.
  • the method for treating a cancer further comprises providing radiotherapy to a subject.
  • the method for treating a cancer further comprises administering to a subject one or more chemotherapeutic agents selected from the group comprising alkylating agents, nitrosoureas, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors.
  • chemotherapeutic agents selected from the group comprising alkylating agents, nitrosoureas, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors.
  • the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention are indicated in monotherapy or combined therapy for the treatment of subjects having a cancer expressing high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • a cancer is for example pancreatic ductal adenocarcinoma (PDA) cancers, melanoma or colon cancers that express high level of UPP1.
  • PDA pancreatic ductal adenocarcinoma
  • melanoma or colon cancers that express high level of UPP1.
  • a test can be carried out to determine whether the cancer to be treated in a subject expresses high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • the present invention provides the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention for use in the treatment of a cancer expressing high level of Uridine phosphorylase 1 (UPP1) or Uridine phosphorylase 2 (UPP2).
  • the treatment further comprises administering one or more cancer immunotherapeutic agents or one or more chemotherapeutic agents or further providing radiotherapy (to the subject).
  • the present invention provides the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention for use in a method of treating a subject with cancer, wherein the method comprises:
  • the immune disorders are selected from inflammation disorders, auto- inflammatory disorders and auto-immune disorders.
  • the inflammation disorders are selected from Rheumatoid Arthritis (RA), Inflammatory Bowel Disease (IBD), Atherosclerosis and Cardiovascular Disease.
  • the auto-inflammatory disorders are selected from TNF Receptor-Associated Periodic Syndrome (TRAPS), Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF).
  • the auto-immune disorders are selected from Systemic Lupus Erythematosus (SLE), Type 1 Diabetes Mellitus, Multiple Sclerosis (MS) and Celiac Disease.
  • the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention can be used in immune modulation. Indeed, the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention can be used to decrease the activity of "over-active" immune cells involved in inflammation disorders, auto-inflammatory disorders and autoimmune disorders, and thus decrease inflammation and prevent auto-inflammatory/auto- immune disorders. Inhibiting (blocking) uridine catabolism can starve those "over-active" immune cells by blocking the access to uridine as energy source and thereby disrupt or reduce their activity.
  • the inventors explored nucleotide catabolism, such as uridine catabolism, in Primary Peripheral Blood Mononuclear Cells (PBMC) and found secretion of lactate (indicative of uridine catabolism for energy production) and survival of the cells in the presence of uridine (see Figure 3). Further, the inventors investigated the efficacy of the compounds of the invention in monocytes-derived macrophages U937 (see Figure 6 that shows that the compounds are active in this context). U937 cells were used as model cells for monocytes (white blood cell), that can be differentiated into macrophages with PMA.
  • PBMC Primary Peripheral Blood Mononuclear Cells
  • the metabolic disorders are selected from fatty liver, obesity and diabetes. Indeed, it is established that a nucleotide-rich diet leads to fatty liver, obesity and diabetes. Thus blocking nucleotide, such as uridine, catabolism decreases energy absorption and helps prevent metabolic disorders.
  • the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention are also nucleotide transport inhibitors and are used for treating a disease associated with nucleotide transport.
  • the disease associated with nucleotide transport is selected from the group comprising cancer, viral diseases, bacterial diseases, cardiovascular disorders, inflammatory disorders, diabetes, pregnancy diseases, muscular diseases, impotence and parasitic infections.
  • the disease associated with nucleotide transport is selected from the group comprising cancer, viral diseases, bacterial diseases, cardiovascular disorders, inflammatory disorders, diabetes, muscular diseases, impotence and parasitic infections.
  • Nucleotide transport inhibitors can be used in (i) antimetabolite potentiation, (ii) adenosine potentiation, and (iii) host tissue protection.
  • nucleotide transport such as uridine transport
  • nucleotide homeostasis such as uridine homeostasis
  • nucleotide transport inhibitors are important to disrupt, interrupt, or reduce the transport of nucleotide, preferably uridine, into cancer cells and/or into immune cells, preferably into cancer cells.
  • the inhibitors of nucleotide catabolism, preferably uridine catabolism, of the present invention are also inhibitors of nucleotide transport, preferably uridine transport.
  • the inhibitors of the present invention inhibit both nucleotide catabolism, preferably uridine catabolism, and nucleotide transport, preferably uridine transport.
  • Another aspect of the present invention provides an inhibitor of nucleotide catabolism, preferably uridine catabolism, of the present invention for use in a method for treating a disease associated with nucleotide transport, preferably uridine transport.
  • a disease associated with nucleotide transport, preferably uridine transport is a disease wherein inhibition of the nucleotide transport, preferably uridine transport, is beneficial for the treatment of said disease.
  • the present invention provides a method for treating a disease associated with nucleotide transport in a subject, the method comprising administering an inhibitor of nucleotide catabolism, preferably uridine catabolism, of the present invention to the subject.
  • a cell line of interest defines as: a. A cell line with natural or artificial high expression of the UPP1 or UPP2 gene, and/or b. A cell line with ability to grow on media where glucose has been replaced by uridine. For example UACC-257 melanoma cells, AsPCl cells, SW480 cells or U937 cells.
  • uridine For example UACC-257 melanoma cells, AsPCl cells, SW480 cells or U937 cells.
  • glucose-free media For example glucose-free RPMI for UACC- 257.
  • multi -well plates for example 384-well plates
  • the multiwell plates are pre-plated with drugs from the libraries.
  • U ACC-257 cells were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine. Supplemented cells were then plated on 384-well plates pre-coated with compounds from the Prestwick library (Prestwick, 1’280 compounds), a kinase inhibitor library (Sellekchem, 258 compounds), a nucleoside library (Enamine, 320 compounds), or a chemically diverse collection (EPFL, 7’678 compounds) see below. The final concentration of inhibitors is lOpM. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and Z-scores were calculated. Compounds were selected for further investigation based on their Z-scores. See Figure 2.
  • U ACC-257 cells were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine. Supplemented cells were then plated on 384-well plates pre-coated with the 96 best compounds from the screen, at 10 concentrations. The final concentration of inhibitors is 10' 4 to IO’ 8 5 M. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and IC50 were calculated. Compounds were selected for further investigation based on their IC50. See Table 2.
  • AsPCl were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine. Supplemented cells were then plated on 96-well plates pre-coated with the 30 best compounds from the validation. The final concentration of inhibitors is lOpM. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and fold changes were calculated. SW480 were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine. Supplemented cells were then plated on 96-well plates pre-coated with the 30 best compounds from the validation. The final concentration of inhibitors is lOpM. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and fold changes were calculated.
  • U937 were diluted in glucose-free media supplemented with lOmM glucose or lOmM uridine, and 100 nM PMA (phorbol-12-myristate-13-acetate). Supplemented cells were then plated on 96-well plates pre-coated with the 30 best compounds from the validation. The final concentration of inhibitors is lOpM. Prestoblue was added after 72h. Relative Prestoblue fluorescence was measured after 2h and fold changes were calculated.
  • the small molecule inhibitors were identified using the screening method of the invention. 1'280 compounds from the Prestwick library, 320 nucleosides analogs, 258 known kinase inhibitors and 7’678 compounds from a chemically diverse collection were used.
  • UACC-257 melanoma cells were used for the primary screen.
  • Cells were grown on RPMI media supplemented with dialyzed FBS and either of lOmM glucose or lOmM uridine, for 72h in the presence of the small molecule inhibitors.
  • the screen readout was performed using a Prestoblue assay (Life Technologies). The same protocol was applied to AsPCl cells, SW480 cells and U937 cells.
  • the tested compounds are able to prevent the growth of cells on uridine but not on glucose. This is demonstrated by a strong difference between IC50 values obtained on uridine and on glucose.
  • PBMC Primary Peripheral Blood Mononuclear Cells
  • Mubritinib and some derivatives thereof have been tested in UACC-257 melanoma cells (see Figure 9 for results).
  • Mubritinib derivative 2 (E)-4-((4-(4-(lH-l,2,3-triazol-l-yl)butyl)phenoxy)methyl)-2- (styryl)oxazole;
  • Mubritinib derivative 4 (E)-4-((4-(4-(l H-l,2,3-triazol-l-yl)butyl)phenoxy)methyl)-2- ((4-methoxy)styryl)oxazole;
  • Mubritinib derivative 5 4-(4’-methylphenoxymethyl)-2-[(E)-2-(4- trifluoromethylphenyl)ethenyl]-l,3-oxazole;
  • Mubritinib derivative 7 (E)-4-((4-(4-(lH-imidazol-l-yl)butyl)phenoxy)methyl)-2-(4- (trifluoromethyl)styryl)oxazole;
  • Mubritinib derivative 8 (E)-4-((4-(4-(lH-pyrrol-l-yl)butyl)phenoxy)methyl)-2-(4- (trifluoromethyl)styryl)oxazole.
  • Cells were diluted in glucose-free media supplemented with 10M glucose (grey in Figure 9) or lOmM uridine (blue in Figure 9), and treated with the drugs of interest at a lOpM concentration. After 72h, Prestoblue was added. Relative Prestoblue fluorescence was measured after 2h. Fold change in viability compared to untreated control cells.

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Abstract

L'invention concerne un procédé de criblage pour l'identification d'inhibiteurs du catabolisme nucléotidique, tel que le catabolisme de l'uridine, les inhibiteurs identifiés par le procédé de criblage et leur utilisation en oncologie, pour la modulation immunitaire et les troubles métaboliques.
PCT/EP2024/058419 2023-03-30 2024-03-28 Inhibiteurs du catabolisme et/ou du transport de l'uridine à usage thérapeutique Pending WO2024200612A1 (fr)

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WO1991016315A1 (fr) * 1990-04-12 1991-10-31 Brown University Research Foundation Derives de barbituriques au 5-benzyle
WO2002018404A2 (fr) * 2000-08-30 2002-03-07 F. Hoffmann-La Roche Ag Derives de nucleosides
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