WO2025053796A1 - Molécules hybrides entre des dérivés de pyrimidine et l'idasanutlin - Google Patents

Molécules hybrides entre des dérivés de pyrimidine et l'idasanutlin Download PDF

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WO2025053796A1
WO2025053796A1 PCT/TH2024/000004 TH2024000004W WO2025053796A1 WO 2025053796 A1 WO2025053796 A1 WO 2025053796A1 TH 2024000004 W TH2024000004 W TH 2024000004W WO 2025053796 A1 WO2025053796 A1 WO 2025053796A1
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idasanutlin
oxy
diamino
ethylpyrimidin
phenyl
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Nitipol SRIMONGKOLPITHAK
Ekkaphot KHONGKLA
Onanong VORASIN
Chariya PEEYATU
Tanawat PHUMJAN
Nawapan PONGSAPIPATANA
Roonglawan RATTANAJAK
Thanaya SAEYANG
Jarunee VANICHTANANKUL
Thanat TIYASAKULCHAI
Pitchayathida MEE-UDORN
Kanokpol APHICHO
Chayaphat WONGSOMBAT
Netnapa CHAROENSETAKUL
Marie HOARAU
Sumalee Kamchonwongpaisan
Yongyuth Yuthavong
Philip James SHAW
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National Science and Technology Development Agency
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug

Definitions

  • This invention relates to organic chemistry, biotechnology and cellular and molecular biology, and a field relating to hybrid molecules between pyrimidine derivatives and idasanutlin.
  • PROTAC is an important tool for stimulating the degradation of target proteins through this mechanism ( Figure 1).
  • PROTAC is a rational design compound depending on the target proteins that needs to be degraded (Eur. J. Med. Chem., vol. 235, p. 114290, May 2022, doi: 10.1016/j.ejmech.2022.114290., Mol. Microbiol., vol. 117, no. 3, pp. 670-681, Mar. 2022, doi: 10.1111/mmi.l4849., Nat. Rev. Drug Discov., Jan.
  • the hybrid molecules between pyrimidine derivatives and idasanutlin according to this invention is of a Formula (A), wherein:
  • R2 is selected from a linear hydrocarbon having 1 to 10 carbon atoms, a branched hydrocarbon having 3 to 10 carbon atoms, or a cyclic hydrocarbon having 3 to 10 carbon atoms;
  • Rs is selected from hydrogen (H), an alkyl group, or halogen
  • L is selected from -O-R"-, -NH-R"-, -CH 2 CH 2CONH-R"-, or -R"-; wherein R" is selected from -(CH2CH2O) n CH2CH2-, -(CH2) m -, group containing carbocyclic, group containing heterocyclic, group containing alcohol acetylene, or group containing amino acetylene; n is an integer in the range from 1 to 6 and m is an integer in the range from 2 to 10;
  • Figure 3 shows the protein levels of human dihydrofolate reductase (hDHFR) and human thymidylate synthase (hTS) in representative human cells, named KB cells, after being stimulated with various compounds for about 24 hours.
  • Methotrexate (MTX) is used as a positive control in the experiment because it has been proven to stimulate the expression of both proteins.
  • the levels of target proteins from each group are normalized to the levels of total protein to yield accurate expression values.
  • Figure 4 shows the simulated structure of mouse double minute 2 homolog protein of Plasmodium falciparum and the binding between the simulated protein and pyrrolidine, nutlin-3a, and idasanutlin by computer method.
  • A is a comparison of simulated structure and template structure available in the Protein Data Bank.
  • B is a prediction of the binding site of simulated protein.
  • C is the binding region between various compounds and proteins, including associated amino acids.
  • This invention relates to hybrid molecules between pyrimidine derivatives and idasanutlin, designed to induce the degradation of dihydrofolate reductase-thymidylate synthase through the ubiquitin-proteasome system.
  • the hybrid molecules between pyrimidine derivatives and idasanutlin, designed to induce the degradation of dihydrofolate reductase-thymidylate synthase through the ubiquitin-proteasome system, according to this invention is of a Formula (A), wherein:
  • Ri is selected from a linear alkyl group having 1 to 10 carbon atoms, a branched alkyl group having 3 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms;
  • R2 is selected from a linear hydrocarbon having 1 to 10 carbon atoms, a branched hydrocarbon having 3 to 10 carbon atoms, or a cyclic hydrocarbon having 3 to 10 carbon atoms;
  • R3 is selected from hydrogen (H), an alkyl group, or halogen
  • R4 is selected from hydrogen (H), ortho-propanoic acid, or ortho-propanoate (-CH2CH 2 COOR'); wherein R' of said propanoate is selected from a linear alkyl group having 1 to 10 carbon atoms or a branched alkyl group having 3 to 10 carbon atoms;
  • Rs is selected from hydrogen (H), an alkyl group, or halogen
  • L is selected from -O-R"-, -NH-R"-, -CH 2 CH 2CONH-R"-, or -R"-; wherein R" is selected from -(CH2CH2O) n CH2CH2-, -(CH2) m -, group containing carbocyclic, group containing heterocyclic, group containing alcohol acetylene, or group containing amino acetylene; n is an integer in the range from 1 to 6 and m is an integer in the range from 2 to 10;
  • this invention also relates to the method for preparing the hybrid compound between pyrimidine derivatives and idasanutlin according to a
  • step a) comprises the steps of: a-1) mixing 3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5-yl)oxy)proproxy)phenyl) propanoic acid solution with an amidation reagent in a first organic solvent, wherein a concentration of 3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5-yl)oxy)proproxy) phenyl)propanoic acid solution is in the range from 0.01 mM to 1 M; a concentration of the amidation reagent is in the range from 0.15 mM to 3 M; a-2) adding a first base to the mixture obtained from step a-1) and stirring the obtained mixture for 5 to 60 minutes; a-3) adding azido -polyethylene glycoln-amine to the mixture obtained from step a-2), wherein n is an integer in the range from 1 to 6, and stirring the obtained mixture at a temperature ranging
  • step b) comprises the steps of: b-1) mixing the mixture of compound obtained from steps a) with triphenylphosphine in a second organic solvent at a temperature ranging from 25 °C to 40 °C for 15 to 60 minutes; b-2) adding ammonium hydroxide solution (NH4OH) to the mixture obtained from step b- 1), and allow it to react for 8 to 24 hours.
  • step b) a molar ratio of N-(2-(2- azidoethoxy) n ethyl)-3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanamide : triphenylphosphine is in the range from 1.0 : 2.0 to 1.0 : 7:0.
  • step b) further comprises the step of eliminating the second organic solvent contained in the mixture obtained from step b-2) under low pressure, followed by purification through column chromatography.
  • step c) comprises the steps of: c-1) mixing idasanutlin with an amidation reagent in a first organic solvent, wherein a concentration of idasanutlin is in the range from 0.01 mM to 1 M; a concentration of the amidation reagent is in the range from 0.15 to 3 M; c-2) adding a first base to the mixture obtained from step c-1) and stirring the obtained mixture for 5 to 60 minutes; c-3) adding N-(2-(2-aminoethoxy) n ethyl)-3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanamide and stirring at a temperature ranging from 25 °C to 40 °C for 8 to 24 hours.
  • step c) a molar ratio of idasanutlin : amidation reagent : first base : N-(2-(2-aminoethoxy)ethyl)-3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanamide is in the range from 1.0 : 1.5 : 4.0 : 1.2 to 1.0 : 3.0 : 7.0 : 2.5.
  • step c) further comprises the step of extracting the mixture obtained from step c-3) with ethyl acetate and water, and eliminating water residue using sodium sulfate (Na2SO4), and evaporating the first organic solvent under low pressure, followed by purification through column chromatography.
  • Na2SO4 sodium sulfate
  • this invention also relates to the method for preparing the hybrid molecules between pyrimidine derivatives and idasanutlin according to the structure (A), R4 is ortho-propanoic acid, R5 is hydrogen (H), and L is para-O-R”-, comprising steps of: a) alkylation between ethyl 3-(2-(3-((2,4-diamino-6-ethylpyrimidin-5-yl)oxy)propoxy)-
  • Step d-2) is hydrolyzation between the intermediate of ethyl3-(5-(m-(4-((3S,4R,5S)-3-(3- chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2- carboxamido)-3-methoxybenzamido)alkoxy)m-2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanoate obtained from step d-1) and a second base to obtain a product of 3-(5-(m-(4-((3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)- 4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-me
  • VII (VII) (II) wherein X is selected from oxygen or carbon; wherein, when X is carbon, m is an integer in the range from 1 to 3, and when X is oxygen, m is an integer in the range from 1 to 6.
  • step a) a molar ratio of ethyl3-(2-(3-((2,4- diamino-6-ethylpyrimidin-5-yl)oxy)propoxy)-5-hydroxyphenyl)propanoate : dibromo alkane : first base is in the range from 1.0 : 2.0 : 1.5 to 1.0 : 5.0 : 6.0.
  • step a) further comprises the step of extracting the mixture obtained from step a with ethyl acetate and water; and eliminating water residue using sodium sulfate (Na2SO4), and evaporating the first organic solvent under low pressure, followed by purification through column chromatography.
  • Na2SO4 sodium sulfate
  • step c) comprises the steps of: c- 1) mixing ethyl3-(azidoalkoxy) m -2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy) phenyl)propanoate with triphenylphosphine (PPhs) in a second organic solvent at a temperature ranging from 25 °C to 40 °C for 15 to 60 minutes; c-2) adding ammonium hydroxide (NH4OH) to the mixture obtained from steps c-1), and allow it to react for 8 to 24 hours.
  • step c) a molar ratio of ethyl3 -(azidoalkoxy ) m -2- (3-((2,4-diamino-6-ethylpyrimidin-5-yl)oxy)propoxy)phenyl)propanoate : triphenylphosphine is in the range from 1.0 : 2.0 to 1.0 : 7.0.
  • step c) further comprises the step of eliminating the second organic solvent of the mixture obtained from step c-2) under low pressure, followed by purification through column chromatography.
  • step d-1) comprises the steps of: d-1-1) mixing idasanutlin with an amidation reagent in a first organic solvent, wherein a concentration of idasanutlin is in the range from 0.01 mM to 1 M; a concentration of the amidation reagent is in the range from 0.015 mM to 3 M; d -1-2) adding base to the mixture obtained from steps d-1-1) and stirring the obtained mixture for 5 to 60 minutes; d- 1-3) adding ethyl3-(aminealkoxy) m -2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy) phenyl)propanoate to the mixture obtained from steps d-1 -2) and stirring at a temperature ranging from 25 °C to 40 °C for 8 to 24 hours.
  • a molar ratio of idasanutlin : amidation reagent : first base : ethyl3-(aminealkoxy) m -2-(3-((2,4-diamino-6-ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanoate is in the range from 1.0 : 1.5 : 4.0 : 1.2 to 1.0 : 3.0 : 7.0 : 2.5.
  • step d-1) further comprises the step of extracting the mixture obtained from step d-1-3) with ethyl acetate and water; and eliminating water residue using sodium sulfate (Na2SO4), evaporating the first organic solvent under low pressure, followed by purification through column chromatography.
  • Na2SO4 sodium sulfate
  • step d-2) is performed by mixing ethyl3-(5-(m- (4-((3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5- neopentylpyrrolidine-2-carboxamido)-3-methoxybenzamido)alkoxy) m -2-(3-((2,4-diamino-6- ethylpyrimidin-5-yl)oxy)propoxy)phenyl)propanoate intermediate obtained from step d-1) with the second base, and stirring the obtained mixture at a temperature ranging from 25 °C to 40 °C for 0.5 to 4 hours, wherein a concentration of the second base is in the range from 0.5 to 3.0 M in the mixed solvent of water and ethanol, wherein a volume ratio of water : ethanol is in the range from 1.0 :1.0 to
  • step d-2) further comprises the step of eliminating ethanol under low pressure, and adjusting pH of the mixture to 2 to 3 using acid solution to obtain the white product, and filtering to collect the product, and washing with water.
  • the first organic solvent is selected from N,N- dimethyl formamide (DMF), tetrahydrofuran anhydrous, dimethyl sulfoxide (DMSO), acetonitrile, or a combination thereof.
  • the first organic solvent is N,N-dimethyl formamide (DMF).
  • the second organic solvent is selected from pyridine, pyrimidine, or a combination thereof.
  • a concentration of pyridine is in the range from 10% w/v to 30% w/v.
  • the amidation reagent is selected from carbodiimides, phosphonium salts, uronium and guanidinium salts, benzotriazole, or a combination thereof.
  • carbodiimide is selected from l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC1.HC1), N,N'-dicyclohexane carbodiimide (DCC), diisopropylcarbodiimide (DIC), or a combination thereof.
  • EDC1.HC1 l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DCC N,N'-dicyclohexane carbodiimide
  • DIC diisopropylcarbodiimide
  • carbodiimide is l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride.
  • phosphonium salt is benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).
  • uronium and guanidinium salt is hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU).
  • benzotriazole is selected from hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), 2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), or a combination thereof.
  • benzotriazole is hydroxybenzotriazole (HOBt).
  • the first base is selected from N,N- diisopropylethylamine (DIPEA), triethylamine (TEA), or a combination thereof
  • the first base is N,N-diisopropylethylamine.
  • the second base is metal hydroxide.
  • metal hydroxide is selected from lithium hydroxide (LiOH) or sodium hydroxide (NaOH).
  • the preparation method of the hybrid molecules between pyrimidine derivatives and idasanutlin having a Formula (I), comprises the steps of:
  • Example 6 (step 3 of Diagram 2): Preparation of ethyl3-(5-(2-(2-aminoethoxy)ethoxy)-2-(3- ((2,4-diamino-6-ethylpyrimidin-5-yl)oxy)propoxy)phenyl)propanoate of a Formula (VUb).
  • N,N- diisopropylethylamine (0.1 ml, 0.6 mmol) was added to the mixture and stirred for about 5 minutes, followed by adding ethyl3-(5-(2-(2-aminoethoxy)ethoxy)-2-(3-((2,4-diamino-6- ethylpyrimidin-5- yl)oxy)propoxy)phenyl)propanoate (62.9 mg, 0.15 mmol). The mixture was further stirred at room temperature for 18 hours. Then, the resulting mixture was subjected to multiple extractions with ethyl acetate and water, and water residue was removed using sodium sulfate (Na2SO4).
  • DIPEA N,N- diisopropylethylamine
  • Table 2 shows the X H, 13 C, 19 F NMR spectrum and molecular weight (ESI-HRMS) of the hybrid compounds, which were synthesized according to Diagram 2. Efficacy test in reducing amounts of dihydrofolate reductase-thymidylate synthase (DHFR- TS) in Plasmodium falciparum.
  • DHFR- TS dihydrofolate reductase-thymidylate synthase
  • Efficacy test of nine synthesized hybrid compounds of P218 and idasanutlin, including P218 alone and idasanutlin alone, in the reduction of dihydrofolate reductase-thymidylate synthase (DHFR-TS) in Plasmodium falciparum was conducted using Western blot analysis.
  • Plasmodium falciparum in the ring stage approximately 12 to 15 hours after entering red blood cells (Figure 2), was used to evaluate the effect of the synthesized hybrid compounds. Plasmodium falciparum was treated with the synthesized hybrid compounds at a concentration of 1 pM for 24 hours. During this timeframe, the parasites would be matured or in the trophozoite stage, and the expression of target protein, dihydrofolate reductase-thymidylate synthase, increased.
  • Table 3 shows percentage of the remaining dihydrofolate reductase-thymidylate synthase (DHFR- TS) in Plasmodium falciparum after treating with the synthesized hybrid compounds of P218 and idasanutlin compared to P218 alone or idasanutlin alone.
  • the values are presented as mean ⁇ standard deviation, derived from at least three independent biological samples.
  • DHFR dihydrofolate reductase
  • the values are presented as mean ⁇ standard deviation, derived from at least three independent biological samples.
  • Plasmodium falciparum in growing trophozoite stage (aged 30 to 40 hours after entering red blood cells, as shown in Figure 2), was cultured for the study. As the expression of dihydrofolate reductasethymidylate synthase was higher in the growing trophozoite stage than in other stages, it was deemed suitable for studying the mechanism of action of compounds in a shorter period of time.
  • the cultured parasites were treated with different concentrations of BION106 for 4 hours, and then protein extraction was performed to measure the remaining protein through Western blot analysis. The results are shown in Table 6.
  • BION106 demonstrated the ability to degrade dihydrofolate reductase-thymidylate synthase with dose-dependent degradation. BION106 can significantly reduce the amount of target protein at a concentration of 10 pM within 4 hours (P-value ⁇ 0.0001).
  • BION 106 The ability of BION 106 in reducing the levels of dihydrofolate reductase-thymidylate synthase in Plasmodium falciparum, is shown in Table 7.
  • the cultured parasites were treated with BION106 at a concentration of 10 pM for varying durations, as outlined in Table 7 (30 to 240 minutes).
  • After the cultured parasites were treated with BION106 for only 30 minutes, it reduced a haft amount of dihydrofolate reductase-thymidylate synthase (% Degradation 46. 76 ⁇ 6.77).
  • Plasmodium falciparum was treated with proteasome inhibitor, 10 pM of bortezomib or 0.5 pM of epoxomicin, as defined in Table 8. This pre-treatment spanned a duration of 2 hours, aiming for the complete inhibition of proteasome activity. Subsequently, the parasites were exposed to BION106 at a concentration of 10 pM for 30 minutes. Then, protein was extracted and used for quantifying the remaining amount of dihydrofolate reductasethymidylate synthase through Western blot analysis.
  • the synthesized hybrid compounds of P218 and idasanutlin provided additional effects distinct from P218 alone or idasanutlin alone. It had an effective degradation of dihydrofolate reductase-thymidylate synthase enzyme in Plasmodium falciparum, through the ubiquitin-proteasome system. In addition, these hybrid compounds exhibited a more selective inhibition of the activity of dihydrofolate reductase- thymidylate synthase in Plasmodium falciparum, compared to human. Additionally, the toxicity was also high in Plasmodium falciparum.
  • Table 6 shows the dose-dependent degradation of BION106 in reducing the amount of dihydrofolate reductase-thymidylate synthase in Plasmodium falciparum, over 4 hours.
  • the values are presented as mean ⁇ standard deviation, derived from at least three independent biological samples.
  • Table 7 shows the effect of BION106 on the time-course degradation of dihydrofolate reductasethymidylate synthase in Plasmodium falciparum.
  • the values are presented as mean ⁇ standard deviation, derived from at least three independent biological samples.
  • Specificity of the hybrid compound to target proteins (target specificity) of human cells.
  • the synthesized hybrid compounds underwent further investigation to determine whether they specifically influenced the degradation of target proteins only in Plasmodium falciparum, without affecting the target proteins, dihydrofolate reductase and thymidylate synthase, in human cells.
  • the inventor designed an assay to examine the targeted degradation of proteins by hybrid PROTAC compounds in human cells.
  • the representative human cells named KB cells, the cultured cells developed from epidermoid carcinoma of the human oral cavity, were selected as a model due to their expression of the proteins of interest, namely human dihydrofolate reductase (hDHFR) and human thymidylate synthase (hTS).
  • methotrexate which was an anti-cancer and antifolate drug, was used. Similar to P218, MTX also inhibited the activity of dihydrofolate reductase enzyme (DHFR inhibitor). It exhibited specific binding and inhibition of the activity of dihydrofolate reductase enzyme in human cells. Notably, MTX stimulated the up-regulation of the targeted proteins, including thymidylate synthase protein in human cells. Given its well-established impact on increasing the expression of both target proteins in human cells, methotrexate (MTX) was used in this experiment as a positive control in this experiment [EE Abali, NE Skacel, H. Celikkaya, and Y.
  • BION106 PROTAC had target specificity to P218 between malaria parasite and human cells. This is an important feature of PROTAC, which targets only parasite proteins rather than host cells.
  • Table 9 shows relative quantity of human dihydrofolate reductase (hDHFR) and human thymidylate synthase (hTS) in representative human KB cells after treating with each compound for 24 hours. This analysis aims to demonstrate the specificity of BION106, P218 and idasanutlin in influencing the expression of target proteins in human cells. Methotrexate (MTX) was used as positive control for the expression of human dihydrofolate reductase (hDHFR) and human thymidylate synthase (hTS).
  • MTX methotrexate
  • hDHFR human dihydrofolate reductase
  • hTS human thymidylate synthase
  • the level of target proteins of each group was analyzed through relative quantification compared with dimethyl sulfoxide-control using the Image Studio (IS) program from Li-COR, version 5.2.5. The values are presented as mean ⁇ standard deviation, derived on at least three independent biological samples. 2 The statistical significance value was analyzed using One-way ANOVA. Holm-Sidak’s & Dunnett’s multiple comparisons test was performed with GraphPad Prism version 8.
  • Figure 1 illustrated the mechanism of action of PROTAC compounds with a Formula (1) formed by the connection of P218 and idasanutlin.
  • the hybrid compound binds to dihydrofolate reductase-thymidylate synthase and proteins in E3 ligase group, respectively (2).
  • This binding brings two proteins into close proximity.
  • a mechanism known as target ubiquitination is activated (3), signaling that these proteins are to be transported to proteasome-a cellular component having an important role in protein degradation (4). Therefore, dihydrofolate reductase-thymidylate synthase undergo degradation resulting in a decrease in the level of this protein.
  • hybrid PROTAC can stimulate the degradation of target proteins according to this mechanism for several cycles.
  • PROTAC the mechanism of action of PROTAC relies on the proximity of the ternary complex formation of target proteins that need to be degraded and proteins that act as E3 ligase, stimulating the process of target ubiquitination. This is a signal for the target proteins to be degraded by proteasome.
  • P218 mainly targets dihydrofolate reductase-thymidylate synthase of Plasmodium falciparum.
  • idasanutlin targets any type of E3 ligase in the studied malaria parasite. Therefore, this invention has provided further studies to elucidate this aspect.

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Abstract

La présente invention concerne des molécules hybrides entre des dérivés de pyrimidine et l'idasanutlin, conçues pour induire la dégradation de la dihydrofolate réductase-thymidylate synthase par l'intermédiaire du système ubiquitine-protéasome. Les composés hybrides selon la présente invention sont différents de la P218 et de l'idasanutlin, dans la mesure où ils peuvent stimuler la dégradation de la dihydrofolate réductase-thymidylate synthase dans le parasite du paludisme, Plasmodium falciparum, par l'intermédiaire du système ubiquitine-protéasome. Cette capacité est très prometteuse pour divers développements de nouvelles formes de médicament destinées au traitement et à la prévention du paludisme. Elle sert également de concept fondamental pour le développement de nouveaux médicaments antipaludiques à l'aide de la technologie PROTAC pour cibler et dégrader d'autres protéines cibles.
PCT/TH2024/000004 2023-09-04 2024-02-08 Molécules hybrides entre des dérivés de pyrimidine et l'idasanutlin Pending WO2025053796A1 (fr)

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