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PARP1 protein degradation agent and application thereof in tumor resistance

A technology of anti-tumor drugs and compounds, applied in the direction of anti-tumor drugs, peptide/protein components, medical preparations containing active ingredients, etc., can solve problems such as recovery, drug action mechanism is not completely clear, and reduce efficacy Toxicity, induction of tumor cell apoptosis, and enhancement of chemotherapy efficacy

Active Publication Date: 2020-09-01
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Secondly, the mechanism of drug action is not completely clear
Third, long-term use of PARP can easily lead to the generation of tumor drug resistance, thereby reducing the curative effect
In addition, loss of 53BP1 expression and multidrug resistance also partially restore HR function

Method used

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  • PARP1 protein degradation agent and application thereof in tumor resistance
  • PARP1 protein degradation agent and application thereof in tumor resistance
  • PARP1 protein degradation agent and application thereof in tumor resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] 1. Preparation of PARP1 ligand intermediate

[0056] Add L (4.45g, 15mmol), N-Boc-piperazine (3.35g, 18mmol) into a round bottom flask, add 100mL of DMF and cool the reaction solution to 0°C. TEA (4.2mL, 30mmol) and HATU (6.80g, 18mmol) were added under stirring, and the reaction was incubated for 5h. After the complete reaction of the raw materials was monitored by TLC, 500 mL of water was added to the reaction liquid, and stirred at 0°C for 1 h. A large amount of white solid was obtained by suction filtration, and the filter cake was washed with a small amount of ice water and ice EA to obtain a crude intermediate (6.43 g, 92% yield).

[0057] Add the above reaction crude product (6.43 g, 13.8 mmol) into a round bottom flask, add 50 mL of absolute ethanol, add 6N HCl (6.9 mL) dropwise under rapid stirring, and react at room temperature for 3 h after the dropwise addition. Concentrate the solvent after TLC monitors that the reaction is complete, add 50mL of water, an...

Embodiment 2

[0114] Example 2 Synthesis of PARP1 PROTAC molecules

[0115] General procedure E: Add V1 / V2 / V3 (0.11mmol) to a 25mL reaction flask, add 10mL DCM / MeOH (5:1) to dissolve, add dropwise 1mL 4M HCl-dioxane solution, react at room temperature for 2h, reduce After concentrating the solvent to obtain a white solid, add L2-L14 (0.1 mmol) to the reaction flask, then add 10 mL of anhydrous DMF to dissolve, put it in an ice-water bath, add DIPEA (0.2 mmol), and add HATU (380 mg, 0.1mmol), the reaction was placed in an ice-water bath for 1-2h. After the completion of the reaction monitored by TLC, 50 mL of semi-saturated brine was added to the reaction solution for dilution, and then extracted with ethyl acetate (3 × 60 mL), the combined organic layers were washed once with saturated aqueous sodium chloride solution, and anhydrous Na 2 SO 4 Dry, filter and distill off the solvent under reduced pressure to obtain an oily crude product. Finally, a white solid was obtained by column chrom...

Embodiment 3

[0117] The synthesis of PV6 refers to the general procedure E, and the product PV6 can be obtained as a white solid with a yield of 74% by using L7 and V1 as the reaction raw materials. 1 H NMR (400MHz,DMSO)δ12.59(s,1H),8.98(s,1H),8.63–8.51(m,1H),8.27(d,J=7.7Hz,1H),7.97(d,J= 7.9Hz, 1H), 7.90(t, J=9.9Hz, 2H), 7.83(t, J=7.4Hz, 1H), 7.49–7.32(m, 6H), 7.23(t, J=9.0Hz, 1H) ,5.13(s, 1H),4.53(d,J=9.2Hz,1H),4.48–4.38(m,2H),4.39–4.29(m,3H),4.28–4.17(m,1H),3.71–3.46 (m,6H), 3.42–3.36(m,2H),3.34(s,6H),3.17(d,J=25.0Hz,2H),2.61–2.53(m,2H),2.47–2.34(m,4H ),2.09–1.98 (m,1H),1.94–1.86(m,1H),0.94(s,9H).HRMS(DART-TOF)calculated for C 46 h 51 FN 8 NaO 7 S + [M+Na] + m / z 901.3483, found 901.3491. Its chemical structural formula is:

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Abstract

The invention discloses a PARP1 protein degradation agent and application of the PARP1 protein degradation agent in tumor resistance. The degradation agent comprises a compound with a structural formula shown in the specification, wherein L is a hydrophobic connection unit; and B is an E3 ubiquitin ligase ligand. The PARP1 protein degradation agent prepared by the invention can effectively degradePARP1 protein, inhibit cell proliferation and induce tumor cell apoptosis. Meanwhile, when the PARP1 protein degradation agent is combined with chemotherapeutic drugs, the effect of enhancing the chemotherapeutic efficacy is achieved, and almost no physiological toxicity exists; and the compound is expected to provide an ideal way for treatment of various diseases caused by PARP1 excessive activation.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a PARP1 protein degradation agent and its application in antitumor. Background technique [0002] During the whole life process, the genomic DNA of organisms is often affected by exogenous and endogenous factors, resulting in DNA damage, which makes genomic DNA unstable and affects the normal replication and expression of genes, thereby Affect the normal physiological activities of the living body, and even cause the body to become cancerous. This damage is mainly divided into two types: endogenous damage and exogenous damage. Endogenous damage includes misreplication, base mutation, reactive oxygen species (RSO) production, and cell metabolites; exogenous damage includes chemical damage. Poisons (such as alkylating agents, etc.), ray radiation, etc. Studies have shown that each cell produces an average of 1×10 per day 4 In order to maintain normal phys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K5/033C07K5/027C07K5/083C07D401/14A61K38/05A61K38/06A61K31/496A61K31/4188A61K33/24A61P35/00
CPCC07K5/06034C07K5/021C07K5/0205C07K5/0806C07D401/14A61K31/496A61K31/4188A61K33/24A61P35/00A61K38/00A61K2300/00
Inventor 曹超国陈元伟
Owner SICHUAN UNIV
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