Synthesis method and application of targeted degradation chimeric compound

Abstract

The invention discloses a targeted degradation chimeric compound as well as a preparation method and application thereof. According to the invention, a photosensitizer capable of generating singlet oxygen and a protein targeting binding agent are connected through a connector to synthesize a degradation targeting chimera. These chimeras can selectively degrade target proteins, cell lysates and target proteins in living cells under illumination and induce death of lesion cells. Meanwhile, in order to increase the permeability of the chimera to cells, in-situ click is carried out in the cells by utilizing a biological orthogonal reaction, so that the target protein is better degraded. Therefore, a new choice is provided for future targeted therapy.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a compound for targeted degradation of SHP2, and a preparation method and application thereof. Background Art

[0002] Src homology 2 domain protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase 1 encoded by the PTPN11 gene. PTPN11 is the first non-receptor oncogene in the PTPs family and is widely expressed in the cytoplasm of various cell types and tissues. Its activation and inactivation mutations are believed to be associated with a variety of solid tumors, including melanoma, breast cancer, non-small cell lung cancer, and colon cancer. SHP2 is involved in a variety of important signal transduction processes in cell biology, participates in the regulation of T cell signals, inhibits T cell activation, and promotes tumor cell escape. At present, SHP2 inhibitors (JAB-3312) have entered clinical phase III and are used in combination with KRAS inhibitors to treat non-small cell lung cancer. In addition, SHP2 protein-targeted hydrolysis chimeric complexes (PROTACs) have also been developed. However, PROTACs targeting SHP2 degraders have low selectivity, drug resistance, and systemic toxicity in vivo, and their drug efficiency is low. This makes it impossible for these PROTAC molecules to achieve the desired therapeutic effect.

[0003] Photodynamic therapy is widely used in drug delivery due to its advantages such as non-invasiveness, simple remote control, and high spatiotemporal resolution. In traditional photodynamic therapy, photosensitizers produce highly active 1 O2 or ROS, which can react with proteins, leading to amino acid oxidation or backbone cleavage. 1 O2 is highly active, it is locally reactive and can only react with proteins within the nanometer range. Compared with traditional PROTAC molecules, photodegradation targeting chimeras (PDTACs) consist of three functional modules, a targeting ligand that binds to the protein of interest (POI), a photosensitizer (PS) that produces reactive oxygen species (ROS) under light irradiation, and a linker that connects the first two parts. Therefore, we designed and synthesized a PDTAC compound for targeted photodegradation of SHP2, which not only has the advantages of non-invasiveness, simple remote control, and high spatiotemporal resolution, but also solves the problems of systemic toxicity and drug resistance of traditional PROTAC molecules.

[0004] In addition to utilizing the advantages of PDTAC, in order to increase the permeability of the chimera to cells, we also used bioorthogonal reactions to click in situ within the cell, thereby better degrading the SHP2 protein, greatly improving the selectivity and spatiotemporal controllability of PDTAC, and providing a strategy for efficient and selective degradation of SHP2. Summary of the invention

[0005] Based on this, the present invention discloses a PDTAC molecule for targeted photodegradation of SHP2, a preparation method and an application thereof, and finds that Bodipy-SHP2 can rapidly degrade SHP2 after light activation, and exhibits obvious phototoxicity and low dark toxicity in tumor cell lines such as Hela, with excellent spatiotemporal controllability, providing a strategy for efficient and selective degradation of SHP2.

[0006] The PDTAC compound we designed and synthesized for targeted photodegradation of SHP2 is not only non-invasive, simple to remotely control, and has high spatiotemporal resolution, but also solves the problems of systemic toxicity and drug resistance of traditional PROTAC molecules.

[0007] In addition, we also used the SPAAC bioorthogonal reaction (Click) to functionalize SHP2-05 with azide (N3) to synthesize the SHP2-05-N3 (05-N3) molecule. Then we connected a DBCO to the photosensitizer to synthesize Bodipy-DBCO (B-DBCO) and CE6-DBCO (C-DBCO). When it enters the cell, it will undergo a bioorthogonal reaction with the N3 tag on the SHP2 protein, thereby bringing the photosensitizer and SHP2 protein closer and achieving the function of photodegradation.

[0008] The present invention provides a compound represented by the general formula (IV) or a pharmaceutically acceptable salt or hydrate thereof: , The compound is composed of SHP2 inhibitor SHP2-05, photosensitizer BODIPY or CE6 and linker, which can specifically recognize SHP2 and label it, so that SHP2 can be recognized and photodegraded. The compound for targeted photodegradation of SHP2 has high specificity and good efficacy, and can be used to prepare anti-tumor drugs, which can produce highly active 1O2 or ROS, thereby effectively reducing the protein level of SHP2 in tumor cells and producing photodynamic therapy, thereby inhibiting the proliferation of tumor cells.

[0009] For compounds II and IV for targeted photodegradation of SHP2, the present invention is achieved by the following technical solutions: (1) Preparation of Compound II: ; Commercially available p-hydroxybenzaldehyde was reacted with 2,4-dimethylpyrrole and then complexed with boron trifluoride ether to obtain intermediate 9, which was then subjected to nucleophilic substitution with 4-methylbenzenesulfonic acid 3-azidopropyl ester, Staudinger reduction, and NIS iodination to obtain intermediate 12, which was finally reacted with DBCO-NHS active ester to obtain Bodipy-DBCO.

[0010] (2) Preparation of compound IV: ; Intermediate 9 was subjected to nucleophilic substitution with 4-alkyn-1-yl-4-methylbenzenesulfonic acid pentyl ester and NIS iodination to obtain intermediate 15, which was then subjected to click chemistry reaction with intermediate 7 and the Boc protecting group was removed by trifluoroacetic acid to obtain the target compound Bodipy-SHP2.

[0011] Compared with the prior art, the present invention has the following beneficial effects: (1) Compared with traditional PROTACs, the PDTAC molecules synthesized in the present invention have a high degree of spatiotemporal controllability, which can significantly reduce the potential off-target effects of PROTACs, and can efficiently and selectively degrade SHP2 protein to induce tumor cell death; (2) These chimeras consist of a ligand that targets the protein of interest, a photosensitizer, and a linker that connects the first two parts. In photodynamic therapy, ROS generated by PS, especially singlet oxygen (1O2), react promiscuously with biomolecules including proteins. 1 O 2 POIs have short lifetimes and diffusion distances, which limit their effective range to within tens of nanometers where they are generated. To exploit this local reactivity, targeting ligands bound to POIs can direct most of the light-induced 1 O 2 Acting on the target protein. 1 O 2 It has high reactivity to amino acid oxidation or backbone cleavage, and POI may be inactivated or even degraded; (3) In terms of molecular structure design, we chose SHP2-05 as the targeting ligand of PDTAC. It is the ligand of the previously reported SHP2 PROTAC molecule SHP2-D26. It has a high affinity for SHP2 and can be used to target SHP2 protein. Then we chose two molecules, pyrrole boron (Bodipy) and porphyrin (CE6), as photosensitizers. They are both relatively mature photosensitizers that have been reported in articles to produce singlet oxygen after illumination. Through the results of biological activity experiments, we found that Bodipy has a stronger effect than CE6. Secondly, the length of the linker is also critical. In the end, we chose to use a relatively short linker to connect the ligand and the photosensitizer; (4) In addition, we also used the SPAAC bioorthogonal reaction to functionalize SHP2-05 with azide (N3) to synthesize the SHP2-05-N3 (05-N3) molecule. When 05-N3 enters tumor cells, it can target and bind to the SHP2 protein, making SHP2 carry the N3 tag. Then we connected a DBCO to the photosensitizer to synthesize Bodipy-DBCO (B-DBCO) and CE6-DBCO (C-DBCO). When it enters the cell, it will react with the N3 tag on the SHP2 protein to bring the photosensitizer and SHP2 protein closer, thus achieving the function of photodegradation. There are two advantages of using bioorthogonal reactions. First, the originally large PDTAC chimera molecule can be split into two smaller molecules, making it easier to enter the cell; second, the original PDTAC molecule is connected to a larger molecule on SHP2-05. Such modification may weaken the binding ability of SHP2-05 with SHP2 protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required to be used in the embodiments of the present invention will be described below.

[0013] Figure 1 This is the schematic diagram of the PDTAC technology principle; Figure 2 is the H NMR spectrum of the compound represented by formula (IV) synthesized in Example 1 of the present invention; Figure 3 This is a graph showing the singlet oxygen production capacity of B-DBCO and B-SHP2 synthesized in Example 1 of the present invention; Figure 4 It is a graph of the degradation ability of B-DBCO and C-DBCO synthesized in Example 1 of the present invention with 05-N3 in situ clicking or direct targeting of B-SHP2 and C-SHP2 synthesized in Example 1 of the present invention at the protein level against SHP2; Figure 5 It is a result diagram of the selectivity of B-DBCO synthesized in Example 1 of the present invention and 05-N3 in situ clicking or direct targeting of B-SHP2 and C-SHP2 synthesized in Example 1 of the present invention to SHP2 at the protein level; Figure 6 It is a schematic diagram of the change of thermal stability of B-SHP2 synthesized in Example 1 of the present invention in the cell lysate layer in response to SHP2; Figure 7 It is a schematic diagram of the concentration-dependent degradation experiment of SHP2 in the cell lysate layer when B-DBCO synthesized in Example 1 of the present invention is clicked with 05-N3 in situ or B-SHP2 and C-SHP2 synthesized in Example 1 of the present invention are directly targeted; Figure 8 It is a schematic diagram of the light-time-dependent degradation experiment of SHP2 in the cell lysate layer under the condition of in situ clicking of B-DBCO synthesized in Example 1 of the present invention with 05-N3 or direct targeting of B-SHP2 synthesized in Example 1 of the present invention; Fig. 9 It is a confocal image of the ability of B-SHP2 synthesized in Example 1 of the present invention to enter cells and the ability of B-DBCO synthesized in Example 1 of the present invention to produce singlet oxygen in cells when in situ clicking with 05-N3 or direct targeting of B-SHP2 synthesized in Example 1 of the present invention; Fig.10 It is a schematic diagram of the concentration-dependent degradation experiment of SHP2 at the cellular level when B-DBCO synthesized in Example 1 of the present invention is clicked with 05-N3 in situ or B-SHP2 synthesized in Example 1 of the present invention is directly targeted; Fig.11 It is a schematic diagram of a time-dependent degradation experiment of SHP2 at the cellular level in the case of in situ clicking of B-DBCO synthesized in Example 1 of the present invention with 05-N3 or direct targeting of B-SHP2 synthesized in Example 1 of the present invention; Fig.12 It is a confocal schematic diagram of the degradation ability of SHP2 at the cellular level when B-DBCO synthesized in Example 1 of the present invention is clicked with 05-N3 in situ or B-SHP2 synthesized in Example 1 of the present invention is directly targeted; Fig.13 This is a graph showing the results of the normal cell and tumor cell toxicity test of B-SHP2 synthesized in Example 1 of the present invention; Fig.14 It is a schematic diagram of the expression of SHP2 downstream genes when B-DBCO synthesized in Example 1 of the present invention is clicked in situ with 05-N3 or B-SHP2 synthesized in Example 1 of the present invention is directly targeted; Fig.15 This is a confocal image of the co-localization of B-SHP2 synthesized in Example 1 of the present invention with three organelles in the cell. DETAILED DESCRIPTION

[0014] The following examples are intended to illustrate the present invention rather than to further limit the present invention. The present invention is further described in detail below with reference to the examples, but the present invention is not limited to these examples and the preparation methods used. Moreover, those skilled in the art can carry out equivalent substitution, combination, improvement or modification to the present invention based on the description of the present invention, but these are all included in the scope of the present invention.

[0015] The compounds II and IV for targeted photodegradation of SHP2 are specifically prepared by the following steps: Example

[0016] Preparation of Compound II Bodipy-DBCO , Synthesis of 4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborolin-10-yl)phenol (9): 4-Hydroxybenzaldehyde (0.37 g, 3.0 mmol) and 2,4-dimethylpyrrole (0.63 g, 6.6 mmol) were dissolved in dry THF (90 mL). Then, a few drops of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 10 hours. Then, a solution of DDQ (0.68 g, 3.0 mmol) in THF (120 mL) was added. The mixture was stirred for 4 hours. After TEA (9 mL, 0.08 mol) was added, boron trifluoride etherate (9 mL, 0.08 mol) was added dropwise to the mixture, and the reaction was allowed to proceed overnight at room temperature, and the THF solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and the solution was washed with 5% sodium bicarbonate aqueous solution (100 mL), and then with water (2×100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EA = 3: 1) to obtain 560 mg of a red solid with a yield of 53%.

[0017] Synthesis of 10-(4-(3-azidopropoxy)phenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4L4,5L4-dipyrrolo[1,2-C:2',1'-F][1,3,2]diazaborolinyl (10): Compound 9 (1.0 g, 2.9 mmol) was dissolved in dry acetonitrile, and potassium carbonate (1.2 g, 8.8 mmol) and 1-[(3-azidopropoxy)sulfonyl]-4-methylbenzene (0.9 g, 3.5 mmol) were added. The mixture was heated to 80°C for 3 hours. After quenching with water (80 mL) and extracting with ethyl acetate (50 mL x 3), the organic layer was washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain 0.5 g of a yellow solid with a yield of 41%.

[0018] Synthesis of 3-(4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborolin-10-yl)phenoxy)propan-1-amine (11): A solution of compound 10 (0.5 g, 2.74 mmol) and triphenylphosphine (0.93 g, 3.55 mmol) in THF (30 mL) was stirred at room temperature overnight. A small amount of water (6 mL) was then added to the mixture. The resulting mixture was vigorously stirred for 4 h and then extracted with ethyl acetate (50 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain 0.48 g of a red oil with a yield of 48%.

[0019] Synthesis of 3-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborolin-10-yl)phenoxy)propan-1-amine (12): Compound 11 (0.43 g, 1.08 mmol) and N-iodosuccinimide (0.61 g, 2.67 mmol) were dissolved in dry DCM (50 mL) and reacted at room temperature for 6 hours. The mixture was washed with saturated aqueous sodium thiosulfate (20 mL) and saturated sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 8:1) to obtain 0.43 g of red oil with a yield of 61%.

[0020] Synthesis of Bodipy-DBCO (13): Compound 12 (50 mg, 0.08 mmol) was dissolved in dry DCM, DBCO-NHS (47 mg, 0.12 mmol) and TEA (24 mg, 0.23 mmol) were added, and the reaction was carried out at room temperature for 30 minutes. Then it was extracted with ethyl acetate (10 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to obtain 41 mg of a red solid with a yield of 55%.

[0021] Example 2 Preparation of compound IV Bodipy-shp2 , Synthesis of 5,5-difluoro-1,3,7,9-tetramethyl-10-(4-(pent-4-yn-1-yloxy)phenyl)-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborine (14): Compound 9 (0.5 g, 1.45 mmol) was dissolved in acetonitrile, and potassium carbonate (0.6 g, 4.40 mmol) and pent-4-yn-1-yl 4-methylbenzenesulfonate (0.4 g, 1.74 mmol) were added. The mixture was heated to 80°C for 3 hours. The mixture was quenched with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated sodium chloride (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=6:1) to obtain 0.39 g of a yellow solid with a yield of 64%.

[0022] Synthesis of 5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-10-(4-(pent-4-yn-1-yloxy)phenyl)-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborine (15): Compound 14 (130 mg, 0.32 mmol) and N-iodosuccinimide (173 mg, 0.77 mmol) were dissolved in dry DCM (10 mL) and reacted at room temperature for 6 hours. The mixture was washed with saturated aqueous sodium thiosulfate (10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=20:1) to obtain 179 mg of a red solid with a yield of 85%.

[0023] Synthesis of N1-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N4-(2-(2-(4-(3-(4-(5,5-difluoro-2,8-diiodo-1,3,7,9-tetramethyl-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborolin-10-yl)phenoxy)propyl)-1H-1,2,3-triazol-1-yl)ethoxy)succinamide (16): Compound 7 (34 mg, 0.05 mmol) and compound 15 (42 mg, 0.06 mmol) were dissolved in 5 mL dry THF, and cuprous iodide (4 mg, 0.02 mmol) and sodium L-ascorbate (118 mg, 0.03 mmol) were added. mg, 0.60mmol) and stirred the reaction mixture at 60°C for 12 hours. Quenched with water (10 mL) and extracted with dichloromethane (5 mL x 3), washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) was added at 0°C. The reaction was stirred for 2 hours and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 3: 1) to give 25 mg of a red solid with a two-step yield of 34%.

[0024] Example 3 Verification of the degradation ability and selectivity of PDTAC on SHP2 protein in vitro (1) The ability of B-DBCO and B-SHP2 to produce singlet oxygen in vitro was indirectly verified by the reduction of DPA ( Figure 3 ); (2) Immunoblotting experiments clarified whether these PDTACs could photodegrade SHP2: We used Coomassie blue-based Bradford protein assay to monitor the photodegradation process. The chimeras were heated at 37°C for 4 h in PBS buffer containing 0.1 g / mL SHP2 protein to allow SHP2-05 to accurately target the SHP2 protein. Then, they were irradiated with a laser at a wavelength of 520 nm or 650 nm for 15 min and verified by SDS-PAGE. The results showed that, except for the bioorthogonal reaction between C-DBCO and 05-N3, all chimeras could significantly degrade SHP2 and showed concentration-dependent degradation of the chimeras ( Figure 4 ); (3) Verify the selectivity of the chimera at the protein level: 0.1 g / mL of fetal bovine serum albumin (BSA) was added to the above protein system. The chimera selectively degraded SHP2 without significantly degrading BSA. These results demonstrate that the ligand-targeted photoinduction strategy can effectively and selectively degrade SHP2 ( Figure 5 ).

[0025] Example 4 Verify the ability of PDTAC to degrade SHP2 protein at the cell lysate level (1) Since PDTAC has good photolytic activity and selectivity at the protein level, we tried to use light-induced PDTAC to degrade SHP2 in cell lysates. At the same time, we wanted to verify whether the photodegradation of PDTAC was achieved through cellular pathways (such as the proteasome and lysosome system) or through the action of light-induced ROS; (2) Cell thermal shift assay to verify whether PDTAC molecules enhance the thermal stability of SHP2: Cell thermal shift assay (CTSA) showed that B-SHP2 indeed increased the thermal stability of SHP2, which ensured the targeted binding of the chimera B-SHP2 to SHP2 in living cells ( Figure 6 ); (3) Western Blot (WB) analysis of cell lysates confirmed that both Bodipy chimeras could significantly degrade SHP2 after 15 min of illumination, and showed a clear concentration dependence ( Figure 7 ); (4) Western Blot analysis of cell lysates verified that the degradation of SHP2 was also related to the irradiation time when the chimera concentration was fixed. In the absence of light irradiation, the level of SHP2 was completely unaffected, indicating that the degradation was the result of light-induced ROS. However, C-SHP2 did not show obvious degradation activity, which we speculated was because the binding ability of C-SHP2 to SHP2 was significantly reduced ( Figure 8 ).

[0026] Example 5 Verification of the photodegradation ability of PDTAC on SHP2 protein at the cell level (1) Confocal experiments confirmed that B-SHP2 effectively binds to SHP2 in living cells ( Fig. 9 ); (2) WB analysis of the photodegradation of intracellular SHP2 by PDTAC. As expected, SHP2 was also degraded by B-SHP2 or 05-N3 and B-DBCO irradiation, depending on the irradiation time and chimera concentration. In addition, the bioorthogonal degradation effects of 05-N3 and B-DBCO were superior to those of B-SHP2. It was observed that the chimeras without light irradiation did not affect SHP2 levels, once again confirming the key role of light-induced ROS in this living cell protein degradation ( Fig.10 , Fig.11 ); (3) Confocal experiments verified that PDTAC molecules can degrade SHP2, and the biorthogonal degradation effects of 05-N3 and B-DBCO are better than those of molecules that directly connect PS and ligands using a linker ( Fig.12 ).

[0027] Example 6 SHP2 photolysis induces cell death and activation of inflammation-related genes (1) MTT experiments evaluated the phototherapy-induced cell death of MV4-11 cells with high SHP2 expression and Hela and HL-7702 cells with low SHP2 expression. The results showed that the PDTAC molecule had a higher phototherapy effect in MV4-11 cells with high SHP2 expression, with an IC50 of only 22 nM ( Fig.13 ); (2) q-PCR experiments investigated whether PDTAC affects SHP2 downstream signaling: We treated MV4-11 cells with PDTAC molecules or DMSO vehicle and monitored the levels of glutaminase (GLS) and NLRP3 transcripts. Some literature reports that knocking out the SHP2 gene promotes glutamine hydrolysis and glutathione production by upregulating glutamine metabolism-related genes such as glutaminase (GLS). The NLRP3 inflammasome stimulates SHP2 translocation to mitochondria and promotes SHP2 interaction with adenine nucleotide translocase 1 (ANT1) and its dephosphorylation, which is a central molecule controlling mitochondrial permeability transition. This mechanism prevents the collapse of mitochondrial membrane potential and the subsequent release of mitochondrial DNA and reactive oxygen species, thereby preventing excessive activation of the NLRP3 inflammasome. The results showed that GLS and NLRP3 were significantly upregulated in cells treated with PDTAC molecules, and increased with increasing light exposure time. At the same time, we also found that the expression of the pro-inflammatory cytokine IL-18 was upregulated. This was because after SHP2 was degraded, the negative regulation of SHP2-NLRP3 was destroyed, resulting in uncontrolled activation of inflammasomes and inducing a large amount of IL-18 production ( Fig.14 ); (3) Confocal experiments found that PDTAC exists in various organelles, with the highest concentration in mitochondria. The positive charge on the photosensitizer Bodipy skeleton may make it easier for positively charged molecules to penetrate the mitochondrial membrane, thereby enriching them in mitochondria ( Fig.15 ).

[0028] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as the specific examples, subclasses, and classes of compounds encompassed by the present invention.

Claims

1. A compound for targeted photodegradation of SHP2, comprising a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, ,in, The photosensitizer used was Bodipy or CE6; the SHP2 inhibitor used was SHP-05.

2. A method for preparing a compound for targeted photodegradation of SHP2, characterized in that: include: ， Commercially available p-hydroxybenzaldehyde was reacted with 2,4-dimethylpyrrole and then complexed with boron trifluoride ether to obtain intermediate 9, which was then subjected to nucleophilic substitution with 4-methylbenzenesulfonic acid 3-azidopropyl ester, Staudinger reduction, and NIS iodination to obtain intermediate 12, which was finally reacted with DBCO-NHS active ester to obtain Bodipy-DBCO.

3. A method for preparing a compound for targeted photodegradation of SHP2, characterized in that: include: ， Intermediate 9 was subjected to nucleophilic substitution with 4-alkyn-1-yl-4-methylbenzenesulfonic acid pentyl ester and NIS iodination to obtain intermediate 15, which was then subjected to click chemistry reaction with intermediate 7 and the Boc protecting group was removed by trifluoroacetic acid to obtain the target compound Bodipy-SHP2.

4. A drug for treating a disease associated with abnormal SHP2 activity or expression, characterized in that: The invention comprises the compound for targeted photodegradation of SHP2 as claimed in claim 1.

5. Use of a drug for treating a disease associated with abnormal SHP2 activity or expression in a biological system, characterized in that: The compound II and compound III for targeted photodegradation of SHP2 as claimed in claim 1 undergo an in situ bioorthogonal reaction (Click) in living cells.

6. The compound II and compound III for targeted photodegradation of SHP2 according to claim 5 undergo in situ click in living cells, characterized in that: The molecules that cause click reaction are DBCO and azide.

7. Use of the compound for targeted photodegradation of SHP2 according to claim 1 in a drug for treating diseases associated with abnormal activity or expression of SHP2.

8. The use according to claim 7, characterized in that: The disease associated with abnormal SHP2 activity or expression includes at least one of melanoma, breast cancer, non-small cell lung cancer and colon cancer.

9. The use according to claim 7, characterized in that: The compound targeting photodegradation of SHP2 is used as a single active ingredient or together with other pharmaceutically acceptable active ingredients to constitute the drug for treating diseases associated with abnormal SHP2 activity or expression.

Images