CN109400597B - A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and its preparation method and application - Google Patents

Abstract

A kind of protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and preparation method and application, alkyl dicarboxylic acid and 1-(4-(3-amino-1H-indazol-4-yl)benzene base)-3-(2-fluoro-5-methylphenyl) urea under the condensation of PyBop, obtains the intermediate product with monocarboxylic acid; 2) the intermediate product with monocarboxylic acid and (2S, 4R )-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- Under the condensation effect of HATU, 2-formamide obtains a protein degradation targeting chimera, the preparation method of the protein degradation targeting chimera of the present invention is simple, easy to realize, and has a high yield, and can be applied to the preparation of antitumor drugs, Especially for the preparation of anti-tumor drugs targeting VEGFR-2 kinase.

Description

A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and its preparation Preparation method and application

technical field

The present invention relates to a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 and a preparation method and application thereof.

Background technique

Protein degradation targeting chimeras (PROTACs) have the functions of ubiquitination and degradation of corresponding target proteins (such as VEGFR-2 protein) and polypeptides. The ligand part of the target protein binds to the target protein, the ligand part of the E3 ubiquitin ligase binds to the E3 ubiquitin ligase, and the two parts are connected by the linker, and the activated ubiquitin is transferred to the target protein through the E3 ubiquitin ligase to achieve After selective ubiquitination of target proteins, the final ubiquitinated target proteins are recognized and degraded by the proteasome.

Specifically, protein degradation-targeted chimeras (PROTACs) ubiquitinate and degrade target proteins and polypeptides involving a protein degradation pathway in organisms, the ubiquitin-proteasome system. The ubiquitin-proteasome system is the main pathway of intracellular protein degradation, and is involved in the degradation of more than 80% of intracellular proteins. The protein degradation process of the ubiquitin-proteasome system is as follows: three enzymes are involved in the ubiquitination of target proteins. Namely E1: ubiquitin activating enzyme; E2: ubiquitin conjugating enzyme; E3: ubiquitin ligase. First, E1 activates ubiquitin, and then transmits ubiquitin to E2. Under the action of E3, the ubiquitin molecule is transferred to the target protein to achieve protein ubiquitination. It is finally recognized by the proteasome and degraded into peptides of a certain length.

Targeting chimeras for protein degradation can treat a variety of diseases in a completely different way than traditional small-molecule compounds. Protein degradation targeting chimeras can selectively reduce the level of target proteins in patient cells to treat some diseases by recognizing and ubiquitinating target proteins, followed by proteasomal degradation.

Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor) is a membrane protein expressed by the VEGF gene, belonging to the tyrosine family of proteins, and is a macromolecular protein closely related to malignant tumors. Vascular endothelial growth factor and its receptors are overexpressed in a series of tumor cells, and the receptor family includes three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is mainly involved in the proliferation of vascular endothelial cells and is most widely distributed in cancer cells. A series of studies have confirmed that it can be an effective drug target.

Since 2008, E3 ubiquitin ligases MDM2 (mouse double minute2homologue), clAP1 (cellulr inhibitor of apoptosis), CRBN (cereblon) and VHL (von Hippel-Lindau) ligands and protein ligands have been reported successively. Molecular PROTACs, one of the more effective E3 ubiquitin ligase ligands is the VHL (von Hippel-Lindau) ligand.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 and its preparation method and application.

To achieve the above object, the present invention adopts the following technical solutions:

A protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, the structural formula is as follows:

Among them, n is an integer between 1-20.

A further improvement of the present invention is that n is 3, 8 or 12.

A preparation method of protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, comprising the following steps:

1) Condensation of alkyldicarboxylic acid with 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea in PyBop Under the action, an intermediate product with a monocarboxylic acid is obtained;

2) Intermediate product with monocarboxylic acid with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4 -Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide under the condensation of HATU, obtains a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, the structural formula is as follows:

Among them, n is an integer between 1-20.

A further improvement of the present invention is that the specific process of the step 1) is: dissolving the alkyl dicarboxylic acid and PyBop in dichloromethane, adding triethylamine dropwise, stirring evenly, adding 1-(4-(3 -Amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea, stirred at room temperature for 12 h and then worked up to give an intermediate product with a monocarboxylic acid.

A further improvement of the present invention is that 3.99 mmol of pimelic acid and 3.19 mmol of PyBop are dissolved in 20 mL of dichloromethane, 4.79 mmol of triethylamine is added dropwise, and after stirring uniformly, 1-(4-(3-amino-1H- Indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea 0.799 mmol, stirred at room temperature for 12 h, and then treated to obtain an intermediate product with a monocarboxylic acid.

A further improvement of the present invention is that the specific process of the step 2) is as follows: the intermediate product with the monocarboxylic acid obtained in the step 1) is dissolved in dichloromethane, and (2S, 4R)-1-(((S) is added. )-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, ice bath Stir well, then add DIPEA dropwise, stir well, add HATU, stir at 25 °C for 12 h, and process after the reaction to obtain a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869.

A further improvement of the present invention is that 7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl )-7-oxoheptanoic acid 0.193 mmol was dissolved in 20 mL of dichloromethane, and (2S, 4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl was added -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 0.193mmol, stir well under ice bath, then add DIPEA 0.773mmol dropwise, stir well, add HATU0. 29 mmol, stirred at 25 °C for 12 h, and then processed to obtain a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869.

Application of a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869 in the preparation of a drug for treating or preventing cancer.

A further improvement of the present invention lies in the application of the protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 in the preparation of antitumor drugs targeting VEGFR-2 kinase.

Compared with the prior art, the present invention has the following beneficial effects:

In the present invention, a protein degradation targeting chimera is obtained by linking a biphenylurea VEGFR-2 protein inhibitor and a von Rippel-Lindau (VHL) protein ligand in an E3 ubiquitin ligase complex using an alkyl dicarboxylic acid. The protein degradation targeting chimeras (PROTACs) can selectively induce the degradation of VEGFR-2 protein. The preparation method of the protein degradation targeting chimera of the present invention is simple, easy to realize, and has a high yield.

The small molecule protein degradation targeting chimera in the present invention can carry out ubiquitination labeling on VEGFR-2 protein, induce protein degradation, and the anti-tumor effect is better than that of VEGFR-2 protein inhibitor. Inhibition of VEGFR-2 protein often requires the drug to be maintained at a high concentration for a long time, which may cause serious side effects; while inducing protein degradation requires only a small amount of compound, this process is similar to catalytic reaction, and does not require equimolar amount of drug, Therefore, the use of small-molecule protein degradation targeting chimeras can reduce the dosage of drugs and reduce toxic and side effects. The protein degradation targeting chimera of the present invention has anti-tumor activity in vitro, and can be applied to the preparation of anti-tumor drugs, especially for the preparation of anti-tumor drugs targeting VEGFR-2 kinase.

Description of drawings

Fig. 1 is the synthetic route diagram of the small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention;

Wherein, compound 1 is 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea, and compound 2 is alkyldi Carboxylic acid, compound 3 is an intermediate product with a monocarboxylic acid, compound 4 is (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, compound (X) is a small molecule protein degradation targeting chimera with antitumor activity.

Specifically marked in the figure are:

a. _PyBop , TEA, _CH2Cl2 , rt _; b. HATU, DIPEA, _CH2Cl2 , rt.

Detailed ways

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, which are to explain rather than limit the present invention.

The protein degradation targeting chimeras (PROTACs) involved in the present invention can selectively induce the degradation of VEGFR-2 protein. In the present invention, a protein degradation targeting chimera is obtained by linking a biphenylurea VEGFR-2 protein inhibitor and a von Rippel-Lindau (VHL) protein ligand in an E3 ubiquitin ligase complex using an alkyl dicarboxylic acid. These compounds have the function of inducing the degradation of VEGFR-2 protein and can be used to prepare novel antitumor drugs.

The present invention provides a small molecule protein degradation targeting chimera with antitumor activity, the protein degradation targeting chimera has antitumor activity in vitro, and can be applied to the preparation of antitumor drugs.

The chemical structural formula of the small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention is as follows:

Wherein, n is selected from an integer between 1-20; preferably, n is 3, 8 or 12.

The protein degradation targeting chimera of the present invention comprises:

(2S,4R)-1-((S)-2-(7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-7-oxoheptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(12-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-12-oxododecanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- yl)benzyl)pyrrolidine-2-carboxamide;

(2S,4R)-1-((S)-2-(16-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)- 1H-Indazol-1-yl)-16-oxohexadecylamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5- yl)benzyl)pyrrolidine-2-carboxamide;

The preparation and activity screening method of the candidate drug small molecule protein degradation targeting chimera with anti-tumor activity provided by the present invention will be described in detail below in conjunction with the synthetic route shown in FIG. 1 and specific synthetic examples.

Referring to Figure 1, a method for preparing a protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, comprising the following steps:

1) Alkyl dicarboxylic acid and biphenylurea VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5- Methyl phenyl) urea obtains the intermediate product with monocarboxylic acid under the condensation action of PyBop condensing agent;

2) This intermediate product with monocarboxylic acid interacts with E3 ubiquitin ligase ligand (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxyl -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide obtains the compound represented by general formula (X) under the condensation of HATU condensing agent;

The specific operation of the step 1) is: dissolving the alkyl dicarboxylic acid and PyBop in dichloromethane, slowly adding triethylamine dropwise, stirring for 3 min, and sampling. VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea was added, stirred at room temperature overnight, After the reaction, the organic solvent was spun off under low pressure, an appropriate amount of water was added, and extracted with ethyl acetate. The extracted organic phase was washed and dried, and then the solvent was evaporated under reduced pressure to obtain a crude product. Acid intermediates.

The specific operation of the step 2) is: dissolving the intermediate product with the monocarboxylic acid obtained in the step 1) in dichloromethane, adding (2S, 4R)-1-((S)-2-amino-3 ,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, stirred under ice bath for 5min, then dropwise Add DIPEA, stir for 5 min, add HATU, and stir at 25°C for 12 h. After the reaction is completed, the organic solvent is spun off under low pressure, an appropriate amount of water is added, and extracted with ethyl acetate. The extracted organic phase is washed and dried, and then the solvent is evaporated under reduced pressure. The crude product was obtained, and the crude product was separated by chromatography to obtain the compound represented by the general formula (X).

The application of the small-molecule protein degradation targeting chimera with anti-tumor activity in the preparation of anti-tumor drugs targeting VEGFR-2 kinase.

Example 1

In the structural formula of the small molecule protein degradation targeting chimera with anti-tumor activity, n is 3, and is prepared by the following steps (see Figure 1):

1) Pimelic acid (compound 2) and VEGFR-2 protein ligand 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methyl) Phenyl)urea (compound 1) under condensation with PyBop condensing agent gives 7-(3-amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl) -1H-indazol-1-yl)-7-oxoheptanoic acid (compound 3); the specific process is as follows:

Pimelic acid (0.64 g, 3.99 mmol) and PyBop (1.66 g, 3.19 mmol) were dissolved in 20 mL of dichloromethane, and triethylamine (665 μL, 4.79 mmol) was slowly added dropwise, stirred for 3 min, and then sampled. Add 1-(4-(3-amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea (0.3 g, 0.799 mmol) and stir at room temperature overnight , then the organic solvent was removed under low pressure, an appropriate amount of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (V /V=6/1-3/1) eluted to obtain a white solid, weighing 0.28 g, with a yield of 67.7%.

LCMS(ESI,m/z):518.20[MH] ^-

2) 7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxo Heptanoic acid (compound 3) with E3 ubiquitin ligase ligand (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4 -(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (compound 4) under the condensation of HATU condensing agent to give (2S,4R)-1-((S)-2- (7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxoheptyl amido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound X); The specific process is as follows:

7-(3-Amino-4-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)-1H-indazol-1-yl)-7-oxoheptane The acid (0.1 g, 0.193 mmol) was dissolved in 20 mL of dichloromethane, and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N was added -(4-(4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (0.084 g, 0.193 mmol), stirred under ice bath for 5 min, then DIPEA (132 μL, 0.773 mmol) was added dropwise , stir for 5min, add HATU (0.11g, 0.29mmol), stir at 25°C for 12h, then spin off the organic solvent under low pressure, add an appropriate amount of water, extract with ethyl acetate, dry over anhydrous sodium sulfate, spin off the organic solvent under reduced pressure, The residue was purified by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (V/V=1/1-0/1) to obtain the title compound, weighing 0.11 g, and yield 61.22%.

The structure of the obtained target compound is as follows:

The hydrogen spectrum nuclear magnetic resonance data are: ¹ H NMR (400MHz, DMSO-D6)δ9.28(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.31-8.33( d,1H),δ8.00-8.02(d,1H),δ7.87-7.89(d,1H),δ7.58-7.64(m,3H),δ7.37-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.81-6.84(m,1H),δ5.21(s,2H),δ5.14(d,1H),δ4.53-4.56(d,1H), δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H) ,δ2.29(s,3H),δ2.12-2.19(m,1H),δ2.02-2.06(m,1H),δ1.87-1.94(m,1H),δ1.67-1.75(m ,3H),δ1.50-1.61(m,2H),δ1.34-1.39(m,2H),δ1.24(m,2H),δ0.91(s,9H).

LCMS(ESI,m/z):930.45[MH] ^-

Example 2

In the structural formula of the small molecule protein degradation targeting chimera with antitumor activity, n is 8.

The synthesis steps are the same as those in Example 1.

The structure of the obtained target compound is as follows:

The hydrogen spectrum nuclear magnetic resonance data are: ¹ H NMR (400MHz, DMSO-D6)δ9.28(s,1H),δ8.99(s,1H),δ8.58(s,2H),δ8.31-8.33( d,1H),δ8.01-8.03(d,1H),δ7.85-7.87(d,1H),δ7.58-7.64(m,3H),δ7.40-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.83(m,1H),δ5.21(s,2H),δ5.14(s,1H),δ4.54-4.56(d,1H),δ4. 43-4.45(t,2H),δ4.36(s,1H),δ4.21-4.25(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H),δ2 .29(s,3H),δ2.00-2.12(m,3H),δ1.91-1.92(m,1H),δ1.66-1.71(m,2H),δ1.43-1.55(m,2H) ),δ1.17-1.36(m,14H),δ0.93(s,9H).LCMS(ESI,m/z):1000.55[MH] ^-

Example 3

In the structural formula of the small molecule protein degradation targeting chimera with antitumor activity, n is 12.

Synthesis steps are the same as in Example 1

The structure of the obtained target compound is as follows:

The hydrogen spectrum nuclear magnetic resonance data are: ¹ H NMR (400MHz, DMSO-D6)δ9.27(s,1H),δ8.98(s,1H),δ8.57(s,2H),δ8.30-8.32( d,1H),δ8.00-8.02(d,1H),δ7.83-7.86(d,1H),δ7.57-7.64(m,3H),δ7.37-7.43(m,6H),δ7 .10-7.19(m,2H),δ6.82(m,1H),δ5.19(s,2H),δ5.13-5.14(d,1H),δ4.53-4.56(d,1H), δ4.41-4.47(t,2H),δ4.35(s,1H),δ4.19-4.24(q,1H),δ3.63-3.70(t,2H),δ2.45(s,3H) ,δ2.29(s,3H),δ1.99-2.12(m,2H),δ1.87-1.94(m,1H),δ1.67-1.71(m,2H),δ1.23-1.49(m ,25H),δ0.94(s,9H).

LCMS(ESI,m/z):1056.60[MH] ^-

Example 4

Screening for inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase.

The ADP-Glo luminescence method was used to determine the inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase.

Dilute ATP (10 mM) to 250 μM with Buffer (Tris 80 mM, MgCl 2 20 mM, BSA 0.2 mg/mL, DTT 2 mM); ATP and substrate Poly (4:1 Glu, Tyr) Peptide are prepared by volume 1:1 to prepare ATP (125 μM )-Poly(4:1Glu,Tyr)Peptide(0.5μg/μL) mixed solution; dilute the kinase with Buffer to 1.5ng/μL. The compounds to be tested were prepared into 6 concentration gradient solutions, and 2 μL of ATP-Poly (4:1Glu,Tyr) Peptide solution, 1 μL of sample solution and 2 μL of enzyme solution were sequentially added to the 384-well plate to initiate the reaction. After incubation at 30°C for 60 min, 5 μL of ADP-Glo reagent was added to stop the reaction. Then add 10 μL of KinaseDetection reagent to convert ADP into ATP, incubate at 25°C for 30min, use the chemiluminescence module of PerkinElmer multi-function microplate reader to measure the luminescence value and calculate the inhibition rate.

Numerical processing: inhibition rate=(positive value-administration group value)/(positive value-negative value)×100%;

The experimental results of the compounds are shown in Table 1:

Table 1 Results of inhibitory activity of protein degradation targeting chimeras on VEGFR-2 kinase. (60nM)

It can be seen from Table 1 that the protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 prepared by the present invention has good inhibitory activity.

Example 5

Protein degradation targeting chimeric cellular level activity assay.

The activity of protein degradation targeting chimera cells was detected by MTT assay. The EA.hy926 cells or SMMC-7721 cells in the logarithmic growth phase were digested with 0.25% trypsin to prepare a single cell suspension, which was inoculated in a 96-well plate (2×10 ⁴ cells/well), 180 μL per well. Incubate in a 37°C, 5% CO ₂ constant temperature incubator, and add drugs after 24 h after the cells adhere to the wall. Three duplicate wells were set in each group. The negative control group was added with 20 μL/well of serum-free medium, and the experimental group was added with 20 μL/well of different concentrations of drugs (diluted with serum-free medium), and placed in a constant temperature of 37°C, 5% CO ₂ Continue to cultivate in the incubator. After 72 hours of drug action, carefully aspirate and discard the supernatant, add 200 μL/well of MTT solution (final concentration 0.5 mg/mL) diluted 10 times in serum-free medium, and incubate at 37°C for 4-6 hours, then carefully aspirate the supernatant. , add 150 μL/well of DMSO, and shake well on a destaining shaker for 15 min. The absorbance (OD) value of each well was measured at a wavelength of 490 nm with an enzyme-linked immunosorbent assay.

Numerical processing: inhibition rate=(OD _{negative group-} OD _{administration group} )/(OD _{negative group-} OD _{blank group} )×100%;

The experimental results of some compounds are shown in Table 2:

Table 2 Inhibitory activity of preferred compounds on EA.hy926 cells and SMMC-7721 cells (100nM, 72h)

It can be seen from Table 2 that the chimera prepared by the present invention has better inhibitory activity on EA.hy926 cells and SMMC-7721 cells.

Claims (7)

1. A protein degradation targeting chimera based on a VEGFR-2 inhibitor ABT-869 is characterized in that the structural formula is as follows:

wherein n is an integer between 1 and 20.

2. The VEGFR-2 inhibitor ABT-869-based proteolytic targeting chimera of claim 1, wherein n is 3, 8 or 12.

3. A preparation method of a protein degradation targeting chimera based on a VEGFR-2 inhibitor ABT-869 is characterized by comprising the following steps:

1) the condensation of alkyl dicarboxylic acid and 1- (4- (3-amino-1H-indazol-4-yl) phenyl) -3- (2-fluoro-5-methylphenyl) urea under PyBop gives an intermediate product with monocarboxylic acid; the specific process is as follows: dissolving alkyl dicarboxylic acid and PyBop in dichloromethane, dropwise adding triethylamine, stirring uniformly, adding 1- (4- (3-amino-1H-indazol-4-yl) phenyl) -3- (2-fluoro-5-methylphenyl) urea, stirring at room temperature for 12H, and treating to obtain an intermediate product with monocarboxylic acid;

2) the intermediate product with monocarboxylic acid and (2S, 4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide are condensed under HATU to obtain the protein degradation targeting chimera based on VEGFR-2 inhibitor ABT-869, and the specific process is as follows: dissolving the intermediate product with the monocarboxylic acid obtained in the step 1) in dichloromethane, adding (2S, 4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-formamide, stirring uniformly in ice bath, then dropwise adding DIPEA, stirring uniformly, adding HATU, stirring for 12 hours at 25 ℃, and treating after the reaction is finished to obtain a protein degradation targeting chimera based on a VEGFR-2 inhibitor ABT-869;

the structural formula of the protein degradation targeting chimera is as follows:

wherein n is an integer between 1 and 20.

4. The preparation method of the VEGFR-2 inhibitor ABT-869-based protein degradation targeting chimera according to claim 3, wherein 3.99mmol of pimelic acid and 3.19mmol of PyBop are dissolved in 20m L dichloromethane, 4.79mmol of triethylamine is added dropwise, after stirring uniformly, 0.799mmol of 1- (4- (3-amino-1H-indazol-4-yl) phenyl) -3- (2-fluoro-5-methylphenyl) urea is added, and after stirring for 12H at room temperature, the mixture is treated to obtain an intermediate product with monocarboxylic acid.

5. The preparation method of the VEGFR-2 inhibitor ABT-869-based protein degradation targeting chimera according to claim 3, wherein 0.193mmol of 7- (3-amino-4- (4- (3- (2-fluoro-5-methylphenyl) ureido) phenyl) -1H-indazol-1-yl) -7-oxoheptanoic acid is dissolved in 20m L dichloromethane, 0.193mmol of (2S, 4R) -1- ((S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- (4- (4-methylthiazol-5-yl) benzyl) pyrrolidine-2-carboxamide is added and stirred uniformly under ice bath, then DIPEA0.773mmol is added dropwise and stirred uniformly, HATU0.29mmol is added, and after stirring at 25 ℃ for 12H, the protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 is obtained.

6. Use of a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869, prepared according to the method of any one of claims 3-5, in the preparation of a medicament for treating or preventing cancer.

7. The use of claim 6, wherein the use of a protein degradation targeting chimera based on the VEGFR-2 inhibitor ABT-869 in the preparation of a VEGFR-2 kinase targeted anti-tumor medicament.

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