WO2023151113A1 - Agent de dégradation sélectif de l'histone désacétylase 8, son procédé de préparation et son utilisation dans une activité antitumorale - Google Patents

Agent de dégradation sélectif de l'histone désacétylase 8, son procédé de préparation et son utilisation dans une activité antitumorale Download PDF

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WO2023151113A1
WO2023151113A1 PCT/CN2022/076987 CN2022076987W WO2023151113A1 WO 2023151113 A1 WO2023151113 A1 WO 2023151113A1 CN 2022076987 W CN2022076987 W CN 2022076987W WO 2023151113 A1 WO2023151113 A1 WO 2023151113A1
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朱卫国
黄金波
张俊
许文超
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深圳大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the technical field of drug design and synthesis, in particular to a histone deacetylase 8 selective degradation agent, a preparation method and its application in antitumor activity.
  • PROTAC Protein degradation targeting chimera
  • PROTAC technology Compared with traditional small molecule inhibitors, PROTAC technology has the following significant advantages: From the perspective of mode of action, PROTAC molecules are fundamentally different from traditional inhibitors. Traditional inhibitors use an occupancy-driven mode of action, specifically binding to the cavity of the target protein. This mode requires a higher drug concentration to maintain the occupancy level of the target protein, thereby exerting pharmacological activity and obtaining clinical application value. On the contrary, PROTAC is an event-driven mode of action, which is not affected by the equilibrium occupancy (equilibrium occupancy), and can achieve over 90% target protein degradation at a lower concentration, which is difficult for the occupancy-driven mode. Achieved. Since PROTAC was proposed in 2001, nine such drugs have reached the clinical development stage, among which ARV-471 and ARV-110 protein degradation drugs have entered the second phase of clinical trials.
  • Histone deacetylases are proteases and one of the key enzymes to maintain the balance of histone acetylation in nucleosomes, the basic unit of chromosomes. Under normal conditions, histone acetylation and deacetylation in the nucleus are in a dynamic balance. Once the balance is out of balance, it can lead to abnormal cell cycle and cell metabolism and induce tumors.
  • Histone deacetylase 8 in the HDACs family is involved in multiple key signaling pathways such as the proliferation and apoptosis of tumor cells in vivo and the regulation of genetic information, and has become a potential therapeutic target for various diseases. At the same time, HDAC8 is also an epigenetic gene Effective targets for silent new drug-like molecules. HDAC8 inhibitors inhibit DNA repair mechanisms, arrest cell cycle progression, induce apoptosis and alter gene expression.
  • HDACs inhibitors are broad-spectrum HDACs inhibitors. Due to the non-negligible side effects, it is urgent to develop selective inhibitors or degradation agents. Therefore, it is of great significance to develop degrading drugs that selectively target histone deacetylase 8, but there are no related reports on degrading drugs targeting histone deacetylase 8 so far.
  • the object of the present invention is to provide a selective degradation agent for histone deacetylase 8, a preparation method and its application in anti-tumor activity.
  • the selective degradation agent for histone sirtuin 8 provided by the present invention can degrade sirtuin 8 in tumor cells in a concentration-dependent and significant selective manner without affecting other types of sirtuins.
  • the present invention provides the following technical solutions:
  • a selective degradation agent for histone deacetylase 8 is provided, the degradation agent has at least one compound represented by formulas 11a-11l or a pharmaceutically acceptable salt thereof:
  • the preparation method comprising the following steps:
  • step (2)-(7) is as follows:
  • X is an integer of 1-4
  • m is an integer of 0-4
  • n is an integer of 1-5.
  • the organic solvent is N,N-dimethylacetylamine.
  • step (1) the following steps are also included:
  • reaction solution was extracted with ethyl acetate, the organic phase was washed 3-5 times with saturated brine, the organic phases were combined and concentrated, and after concentration, they were separated and purified by silica gel column to obtain compounds 3a and 3b.
  • the alkaline reagent is sodium hydroxide
  • the acid reagent is acetic acid
  • step (6) the volume ratio of MeOH and THF in the MeOH/THF solution is 1:1.
  • step (7) the volume ratio of isobutanol, N,N-dimethylacetylamine and water in the isobutanol/N,N-dimethylacetylamine/water solution is 1: 2:0.5; the inert gas is nitrogen.
  • a pharmaceutical composition in the third aspect, includes the histone deacetylase 8 selective degradation agent as described in the first aspect.
  • composition also includes pharmaceutically acceptable carriers and/or adjuvants.
  • the pharmaceutical composition of the present invention uses the histone deacetylase 8 selective degradation agent described in the first aspect, does not exclude the change of the preparation system and the way of administration, and performs a simple chemical reaction on the above-mentioned degradation agent. Modified and adjusted derivatives, medicinal salts, multi-compounds, and multi-degradants combined.
  • the pharmaceutically acceptable salts of the above compounds provided by the present invention can be: sodium salt, potassium salt, ammonium salt, amino acid salt, lactate, hydrochloride, phosphate, acetate, apple Salt, citrate or aspartate etc., the present invention does not specifically limit to drug salt.
  • the histone deacetylase 8 selective degradation agent of the present invention can be formulated as an active ingredient in a non-toxic, inert and pharmaceutically acceptable carrier medium; the prepared drug can be prepared by conventional means Administration includes, but is not limited to, oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, or topical administration.
  • the dosage form of the pharmaceutical composition of the present invention is a drug for oral administration, it contains a safe and effective amount of the histone deacetylase 8 selective degradation agent of the present invention and a pharmaceutically acceptable carrier and/or adjuvant , Orally administered medicines can be made into common dosage forms such as tablets, pills, powders, granules, capsules, emulsions, syrups, ointments, suppositories; in the present invention, the carrier and/or adjuvant are not specifically limited.
  • the pharmaceutical composition of the present invention can also be made into injections, which can be made into injections with water for injection, physiological saline, and glucose water under aseptic conditions, and the above-mentioned injections can be prepared by conventional methods.
  • the selective degradation agent of histone deacetylase 8 as described in the first aspect, and the pharmaceutical composition described in the third aspect is used for preventing or treating diseases related to HDAC8 activity or abnormal expression. application in medicine.
  • the above-mentioned related diseases are hematological tumors, solid tumors and other tumors, viral infections and parasitic diseases.
  • the present invention has the following beneficial effects:
  • the selective degradation agent for histone sirtuin 8 provided by the present invention can significantly and selectively degrade sirtuin 8 in tumor cells in a concentration-dependent manner, without affecting other types of sirtuin, suggesting that it plays an important role in The value of preparing drugs for preventing or treating diseases related to HDAC8 activity or abnormal expression, especially anti-tumor active drugs.
  • Fig. 1 is the test result schematic diagram of protein degradation experiment of the present invention
  • Fig. 2 is the test result schematic diagram of the immunofluorescence experiment of A549 cell of the present invention.
  • Fig. 3 is the test result schematic diagram of the immunofluorescence experiment of HCT116 cell of the present invention.
  • Fig. 4 is the test result schematic diagram of cell cloning experiment of the present invention.
  • Fig. 5 is the test result schematic diagram of cell apoptosis experiment of the present invention.
  • Fig. 6 is the test result schematic diagram of cell apoptosis experiment of the present invention.
  • Fig. 7 is a schematic diagram of the test results of the mouse body weight and tumor volume in the mouse transplantation tumor model experiment of the present invention.
  • Fig. 8 is a schematic diagram of the test results of the mouse xenograft tumor model experiment of the present invention.
  • weight content herein can be represented by the symbol “%”.
  • composition means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof or in combination with other active drugs.
  • This embodiment provides the preparation method of the above-mentioned histone deacetylase 8 selective degradation agent, specifically, the preparation method includes the following steps:
  • the synthetic route is as follows:
  • the synthesis method of compound 3b refers to the synthesis method of compound 3a, specifically compound 2b and compound 1 are reacted and synthesized, and compound 3b is obtained as a yellow solid (0.42g) with a yield of 83%.
  • the synthesis method of compound 8b was referred to the synthesis method of compound 8a, specifically by reacting compound 7 with 1,3-dibromopropane.
  • Compound 8b was obtained as a white solid (0.20 g) with a yield of 78%.
  • the synthesis method of compound 8c refers to the synthesis method of compound 8a, specifically by reacting compound 7 with 1,4-dibromobutane to obtain compound 8c as a white solid (0.22g) with a yield of 75%.
  • the synthesis method of compound 8d refers to the synthesis method of compound 8a, specifically by reacting compound 7 with 1,5-dibromopentane to obtain compound 8d as a white solid (0.23g) with a yield of 75%.
  • the synthesis method of compound 8e was referred to the synthesis method of compound 8a, specifically by reacting compound 7 with 1,6-dibromohexane to obtain compound 8e as a white solid (0.22 g) with a yield of 70%.
  • the synthesis method of compound 8f refers to the synthesis method of compound 8a, specifically by reacting compound 7 with 1-bromo-2-(2-bromoethoxy)ethane to obtain compound 8f as a white solid (0.21g) with a yield of 71% .
  • the synthesis method of compound 8g was referred to the synthesis method of compound 8a, specifically by reacting compound 7 with 1,2-bis(2-bromoethoxy)ethane to obtain compound 8g as a white solid (0.27g) with a yield of 80%.
  • the synthesis method of compound 8h refers to the synthesis method of compound 8a, specifically, compound 7 is synthesized by reacting with 1-bromo-2-(2-(2-(2-bromoethoxy)ethoxy)ethane, and the obtained compound 8h is a white solid (0.27 g), yield 72%.
  • the synthesis method of compound 8i refers to the synthesis method of compound 8a, specifically, compound 7 is reacted with 1,14-dibromo-3,6,9,12-tetraoxatetradecane, and compound 8i is obtained as a white solid (0.27g). The yield was 68%.
  • the synthesis method of compound 8j refers to the synthesis method of compound 8a, specifically compound 7 and 1,17-dibromo-3,6,9,12,15-pentaoxaheptadecane were synthesized by reaction, and the obtained compound 8j was a white solid (0.24g), The yield was 61%.
  • the synthesis method of compound 9b refers to the synthesis method of compound 9a, specifically, compound 8b is synthesized by reacting with sodium azide, and compound 9b is obtained as a white solid (0.17g) with a yield of 85%.
  • the synthesis method of compound 9c refers to the synthesis method of compound 9a, specifically by reacting compound 8c with sodium azide to synthesize compound 9c as a white solid (0.17 g) with a yield of 90%.
  • the synthesis method of compound 9d refers to the synthesis method of compound 9a, specifically, compound 8d is synthesized by reacting with sodium azide, and compound 9d is obtained as a white solid (0.16 g) with a yield of 90%.
  • the synthesis method of compound 9e was referred to the synthesis method of compound 9a, specifically by reacting compound 8e with sodium azide to synthesize compound 9e as a white solid (0.18 g) with a yield of 94%.
  • the synthesis method of compound 9f refers to the synthesis method of compound 9a, specifically, compound 8f is synthesized by reacting with sodium azide, and compound 9f is obtained as a white solid (0.18 g) with a yield of 95%.
  • the synthesis method of compound 9g refers to the synthesis method of compound 9a, specifically by reacting compound 8g with sodium azide to synthesize compound 9g as a white solid (0.18g) with a yield of 91%.
  • the synthesis method of compound 9h refers to the synthesis method of compound 9a, specifically, compound 8h is synthesized by reacting with sodium azide, and compound 9h is obtained as a white solid (0.19 g) with a yield of 89%.
  • the synthesis method of compound 9i refers to the synthesis method of compound 9a, specifically by reacting compound 8i with sodium azide to synthesize compound 9i as a white solid (0.21 g) with a yield of 88%.
  • the synthesis method of compound 9j refers to the synthesis method of compound 9a, specifically, compound 8j is synthesized by reacting with sodium azide, and compound 9j is obtained as a white solid (0.19 g) with a yield of 80%.
  • the synthesis method of compound 10b refers to the synthesis method of compound 10a, specifically, compound 9b is synthesized by reaction with hydroxylamine, and compound 10b is obtained as a white solid (0.15 g), with a yield of 85%.
  • the synthesis method of compound 10c refers to the synthesis method of compound 10a, specifically by reacting compound 9c with hydroxylamine.
  • Compound 10c is obtained as a white solid (0.15 g) with a yield of 88%.
  • the synthesis method of compound 10d refers to the synthesis method of compound 10a, specifically, compound 9d is synthesized by reaction with hydroxylamine, and compound 10d is obtained as a white solid (0.15 g) with a yield of 90%.
  • the synthesis method of compound 10e refers to the synthesis method of compound 10a, specifically, compound 9e is synthesized by reaction with hydroxylamine, and compound 10e is obtained as a white solid (0.18 g) with a yield of 92%.
  • the synthesis method of compound 10f refers to the synthesis method of compound 10a, specifically by reacting compound 9f with hydroxylamine to obtain compound 10f as a white solid (0.15 g) with a yield of 95%.
  • the synthesis method of compound 10g refers to the synthesis method of compound 10a, specifically by reacting compound 9g with hydroxylamine to obtain compound 10g as a white solid (0.16g) with a yield of 92%.
  • the synthesis method of compound 10h refers to the synthesis method of compound 10a, specifically, compound 9h is synthesized by reaction with hydroxylamine, and compound 10h is obtained as a white solid (0.17g) with a yield of 90%.
  • the synthesis method of compound 10i refers to the synthesis method of compound 10a, specifically by reacting compound 9i with hydroxylamine to obtain compound 10i as a white solid (0.17g) with a yield of 86%.
  • the synthesis method of compound 10j refers to the synthesis method of compound 10a, specifically, compound 9j is synthesized by reaction with hydroxylamine, and compound 10j is obtained as a white solid (0.18 g), with a yield of 84%.
  • the synthesis method of compound 11b refers to the synthesis method of compound 11a, specifically compound 10b and compound 3a were synthesized by reaction, and compound 11b was obtained as a yellow solid (52 mg) with a yield of 51%.
  • the synthesis method of compound 11c refers to the synthesis method of compound 11a, specifically compound 10c and compound 3a were synthesized by reacting to obtain compound 11c as a yellow solid (52 mg) with a yield of 50%.
  • the synthesis method of compound 11d refers to the synthesis method of compound 11a, specifically compound 10d and compound 3a were synthesized by reacting to obtain compound 11d as a yellow solid (48 mg) with a yield of 45%.
  • the synthesis method of compound 11e refers to the synthesis method of compound 11a, specifically compound 10e and compound 3a were synthesized by reacting to obtain compound 11e as a yellow solid (45 mg) with a yield of 42%.
  • the synthesis method of compound 11f refers to the synthesis method of compound 11a, specifically compound 10f and compound 3a were synthesized by reacting to obtain compound 11f as a yellow solid (70 mg) with a yield of 66%.
  • the synthesis method of compound 11g refers to the synthesis method of compound 11a, specifically compound 10g and compound 3a were synthesized by reacting to obtain compound 11g as a yellow solid (57 mg) with a yield of 51%.
  • the synthesis method of compound 11h refers to the synthesis method of compound 11a, specifically compound 10h and compound 3a were synthesized by reacting to obtain compound 11h as a yellow solid (51 mg) with a yield of 43%.
  • the synthesis method of compound 11i refers to the synthesis method of compound 11a, specifically compound 10i and compound 3a were synthesized by reacting to obtain compound 11i as a yellow solid (47 mg) with a yield of 37%.
  • the synthesis method of compound 11j refers to the synthesis method of compound 11a, specifically compound 10j and compound 3a were synthesized by reacting to obtain compound 11j as a yellow solid (44 mg) with a yield of 33%.
  • the synthesis method of compound 11k refers to the synthesis method of compound 11a, specifically compound 10d and compound 3b were synthesized by reacting to obtain compound 11k as a yellow solid (49 mg) with a yield of 45%.
  • the synthesis method of compound 11l refers to the synthesis method of compound 11k, specifically compound 10f and compound 3b were synthesized by reacting to obtain compound 11l as a yellow solid (43 mg) with a yield of 40%.
  • A549 or HCT116 cells were planted in a 96-well plate, each well containing 5 ⁇ 10 4 cells/100 ⁇ L, and after 12 hours, corresponding doses of degradation agents or DMSO (control wells) were added. After incubating in the incubator for 20 h, 75 ⁇ L of 8% formaldehyde-containing TBS solution was added to each well, and fixed at room temperature for 20 min. Remove the solution, wash twice with 200 ⁇ L/well of TBST, add 50 ⁇ L/well of 0.1% Ttiton in PBS solution, and let stand for 15 minutes. Remove the solution in the 96-well plate, wash twice with 150 ⁇ L/well of TBST.
  • the compounds 11a-11l provided by the present invention can degrade sirtuin 8 in cells in a concentration-dependent manner.
  • A549 cells were treated with the above-mentioned synthetic compounds, they were lysed by adding RIPA under ice bath for 30 minutes, then protease degradation reagent was added, and the protein concentration was quantitatively tested with BCA kit. Take an equal amount of protein and run electrophoresis with 10-12% polyacrylamide. After the protein bands are transferred to a PVDF membrane, they are blocked with 5% skim milk for 1 hour. The target band was blocked with the primary antibody for 12 hours at 4°C, washed and then incubated with the secondary antibody for 1 hour at room temperature, and immediately chemiluminescent imaging was performed after adding the immunofluorescence substrate. The test results are shown in Figure 1.
  • some compounds 11c, 11f, and 11h can significantly and selectively degrade sirtuin 8 in tumor cells in a concentration-dependent manner, while other types of sirtuins such as HDAC1, HDAC2, HDAC3, HDAC6 and Sirt7 proteins were largely unaffected.
  • compound 11f also significantly degrades HDAC8 in tumor cells in a concentration-dependent manner.
  • the results shown in FIG. 4 show that the degradation agent 11f provided by the present invention can affect the colony formation of tumor cells in a concentration-dependent manner.
  • A549 cells were treated with degradation agent 11f, they were stained with Annexin V Alexa Fluor 488 and propidium iodide (PI) for 10 minutes according to the kit instructions, and the apoptosis was analyzed on a flow cytometer.
  • the experimental results are shown in Figure 5 and Figure 6.
  • the degradation agent 11f can induce apoptosis of A549 cells at a concentration ranging from 5 ⁇ M to 20 ⁇ M.
  • mice 5x10 6 A549 cells and 50% Matrigel were injected subcutaneously in the right abdomen of immunodeficient mice.
  • the mice were randomly divided into four groups, 5 in each group.
  • the drug group and the blank group were administered according to the dosage, and injected every 5 days.
  • the radiation dose of the irradiation group was 3G after 20 hours of administration.
  • the growth status of the mice was monitored every day, the tumor volume was weighed and measured once a week, and the corresponding mass and tumor volume were recorded. The experimental results are shown in Figure 7.
  • the tumor tissues were removed, treated with formaldehyde, and numbered for preservation. Part of the tumor tissue was removed, ground with liquid nitrogen, lysed with PIPA, and analyzed by Western blots. In addition, some tumor tissues were fixed with 4% polyformaldehyde for 24 hours, dehydrated and embedded in paraffin. Sections were immunohistostained with HE or corresponding antibodies such as HDAC8 and ⁇ -H 2 AX. The digital slice scanner NanoZoomer S60 was used for testing, and the test results are shown in Figure 8.
  • the compound 11f can significantly inhibit the growth of tumor.
  • the selective degradation agent for histone sirtuin 8 provided by the present invention can significantly and selectively degrade sirtuin 8 in tumor cells in a concentration-dependent manner without affecting other types of deacetylation
  • the enzyme indicates its value in the preparation of drugs for preventing or treating diseases related to HDAC8 activity or abnormal expression, especially anti-tumor active drugs.

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Abstract

Sont divulgués un agent de dégradation sélectif de l'histone désacétylase 8 (HDAC8), son procédé de préparation et son utilisation dans une activité antitumorale, se rapportant au domaine technique de la conception et de la synthèse de médicament. Le agent de dégradation sélectif de HDAC8 peut dégrader de manière significative et sélective HDAC8 dans des cellules tumorales d'une manière dépendante de la concentration, sans affecter d'autres types de désacétylases, ce qui met en évidence la valeur de l'agent de dégradation sélectif de HDAC8 dans la préparation de médicaments pour prévenir ou traiter des maladies associées à une activité ou à une expression anormale de HDAC8, en particulier des médicaments actifs antitumoraux.
PCT/CN2022/076987 2022-02-09 2022-02-21 Agent de dégradation sélectif de l'histone désacétylase 8, son procédé de préparation et son utilisation dans une activité antitumorale WO2023151113A1 (fr)

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