GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug

A protein degradation and reaction technology, applied in the field of anti-tumor cell drugs, to achieve good anti-proliferation effect, good GPX4 degradation effect, and good biological activity.

Active Publication Date: 2021-09-03
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there are no reports of GPX4 inhibitors that have entered the clinical research s

Method used

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  • GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
  • GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug
  • GPX4 protein degradation agent, preparation method and application thereof, and antitumor cell drug

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0128] The present invention provides the preparation method of above-mentioned GPX4 protein degradation agent, comprises the following steps:

[0129] ①When A 1 for hour,

[0130] The preparation method of described GPX4 protein degradation agent comprises the following steps:

[0131] The E3 ligand compound substituted by the azidopolyethylene glycol chain reacts with the first GPX4 ligand to obtain a GPX4 protein degradation agent;

[0132] The azido polyalcohol chain heterocyclic compound has a structure shown in formula A-1, A-2 or A-3:

[0133]

[0134] The first GPX4 ligand has a structure shown in formula B:

[0135]

[0136] In the present invention, the molar ratio of the E3 ligand compound substituted by the azidopolyethylene glycol chain to the first GPX4 ligand is preferably 0.11:0.12; in the present invention, the catalyst for the ring-forming reaction is preferably For sodium ascorbate and copper sulfate, the molar ratio of the sodium ascorbate, copper...

Embodiment 1

[0274] The synthesis of embodiment 1GPX4 protein degradation agent R1

[0275] (1) Synthesis of the first GPX4 ligand

[0276] a. Synthesis of compound shown in formula g

[0277] Dissolve p-formylbenzoic acid (8.00g, 53.29mmol), propiolic acid (4.40g, 79.93mmol) in THF (120mL), then add EDCI (15.32g, 79.93mmol), HOBT (10.80g, 79.93mmol) ), reacted at room temperature for 14h. After the reaction, part of the solvent was rotated off under reduced pressure, extracted three times with water and ethyl acetate, the organic phases were combined, washed with saturated NaCl solution and anhydrous NaCl 2 SO 4 dry. Column separation (P / E=5 / 1, 2 / 1) gave a white solid, and the compound represented by formula g was obtained, which was designated as RSL3-Q1. 1 H NMR (400MHz, DMSO-d 6 )δ10.09(s, 1H, CHO), 9.17(t, J=2.68Hz, 1H, CONH), 7.80-8.06(m, 4H, Ar-H), 4.09(dd, J=5.52, 2.48Hz, 2H, CH 2 ), 3.16(t, J=2.48Hz, 1H, CH); 13 CNMR (400MHz, DMSO-d 6 )δ193.34, 165.61, 139.20, 138.39, 12...

Embodiment 2～4

[0291] The synthesis of embodiment 2~4GPX4 protein degradation agent R2~4

[0292] The difference between Examples 2-4 and Example 1 lies in the difference in the n value of the starting material when preparing the compound having the structure shown in the formula PEG1-7.

[0293] Spectral data of R2: 1 H NMR (400MHz, DMSO-d 6 )δ10.93(s, 1H, NH), 8.91(t, J=7.76Hz, 1H, CONH), 7.74-7.89(m, 3H, Ar-H), 7.46-7.61(m, 3H, Ar-H ), 7.18-7.30(m, 2H, Ar-H), 6.92-7.08(m, 3H, Ar-H), 6.81(d, J=7.88Hz, 1H, Ar-H), 6.02(s, 1H, CH), 5.39 (brs, 1H, CH), 5.18 (dd, J=13.24, 4.92Hz, 1H, CH), 4.72 (d, J=14.00Hz, 1H, CH 2a ), 4.40-4.48 (m, 5H, CH 2 ×2&CH 2b ), 4.11 (q, J=57.08, 16.76Hz, 2H, CH 2 ), 3.73-3.88 (m, 4H, CH 2 ×2), 3.39-3.59(m, 15H, CH 2 ×6&CH 3 ), 2.74-3.04 (m, 2H, CH 2 ), 2.02-2.33 (m, 2H, CH 2 ); 13 CNMR (400MHz, DMSO-d 6 )δ172.13,171.07,169.37,168.20,166.26,159.34,145.53,144.04,136.88,134.27,133.07,132.68,129.31,127.75,126.17,126.12,123.61,123.59,121.81,121.78,119.34,118.48...

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Abstract

The invention provides a GPX4 protein degradation agent, a preparation method thereof, and an anti-tumor cell drug, and belongs to the technical field of drug application. The GPX4 protein degradation agent provided by the invention has a protein degradation targeting chimera (PROTAC) molecular structure, a mother nucleus structure of the GPX4 protein degradation agent is used as a small molecule ligand for combining target protein, an A2 substituent is used as a small molecule ligand for combining an E3 ubiquitin ligase compound, and an A1 substituent is used as a connecting group for connecting the two ligands. The GPX4 protein degradation agent with the structure can specifically recognize GPX4 protein and effectively ubiquitinate and degrade the GPX4 protein, so that tumor cell ferroptosis is induced.

Description

technical field [0001] The invention relates to the technical field of drug application, in particular to a GPX4 protein degradation agent, its preparation method and application, and an anti-tumor cell drug. Background technique [0002] In 2012, Stockwell of Columbia University and others proposed the concept of "ferroptosis", which is an iron-dependent programmed cell death mode characterized by the accumulation of reactive oxygen species in cells. Ferroptosis is often caused by defects in the intracellular lipid hydroperoxide scavenging system, resulting in a large amount of lipid hydroperoxide accumulation, which eventually causes cell damage and death. [0003] During biological evolution, cells have developed a defense mechanism against ferroptosis caused by oxidative lipid accumulation, called the System Xc-_GSH_GPX4 pathway. Glutathione peroxidase 4 (GPX4) is the core protein in the pathway, and it is one of the eight subtypes of the glutathione peroxidase family. ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07K5/062C07K1/113A61K31/4545A61K31/437A61K31/496A61K38/05A61P35/00
CPCC07D471/04C07K5/06034A61P35/00C07B2200/07A61K38/00
Inventor 徐萍王超郑藏鑫孙丹许凤荣
Owner PEKING UNIV
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