CN116462669A - SOS1 and EGFR double-target compound, and preparation method and application thereof - Google Patents

SOS1 and EGFR double-target compound, and preparation method and application thereof Download PDF

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CN116462669A
CN116462669A CN202310733464.2A CN202310733464A CN116462669A CN 116462669 A CN116462669 A CN 116462669A CN 202310733464 A CN202310733464 A CN 202310733464A CN 116462669 A CN116462669 A CN 116462669A
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sos1
cancer
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CN116462669B (en
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牛淼淼
郑禄枫
徐盛涛
周运江
张雨欣
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China Pharmaceutical University
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    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61P35/02Antineoplastic agents specific for leukemia
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Abstract

The invention discloses an SOS1 and EGFR double-target compound and a preparation method and application thereof, and also discloses a pharmaceutical composition, wherein the preparation is prepared from the double-target compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or auxiliary materials, and the compound has SOS1 and EGFR double-inhibition activity, can inhibit proliferation of tumor cells, promote apoptosis of tumor cells, shows excellent in-vivo and in-vitro anti-tumor activity and has better drug-forming prospect.

Description

SOS1 and EGFR double-target compound, and preparation method and application thereof
Technical Field
The invention relates to an SOS1 and EGFR double-target compound, in particular to an SOS1 and EGFR double-target compound, a preparation method and application thereof.
Background
Epidermal Growth Factor (EGF) receptor (EGFR) is a transmembrane protein with tyrosine kinase activity, and binding of growth factor to EGFR activates EGFR, which in turn activates its mediated downstream RAS/AKT pathway, which inhibits apoptosis and promotes proliferation, invasion, metastasis and angiogenesis. In addition, EGFR can mediate progression of the cell cycle by promoting passage of cells through the G1 phase by activating the cyclin dependent kinase 4/6 (CDK 4/6) -cyclin D (cyclin D) complex. EGFR is therefore an important target for prostate cancer intervention. However, numerous studies have shown that overexpression of EGFR is associated with a poor prognosis for prostate cancer. Currently, EGFR-targeting drugs such as gefitinib are already marketed in batches. Gefitinib has been reported to have limited single drug activity against androgen refractory prostate cancer, and its combination with other drugs can improve the therapeutic effect.
SOS1 (son of seveless 1) is a key nucleotide exchange factor for KRAS, converting GDP-bound KRAS (inactive) to GTP-bound KRAS (active form); SOS1 has been identified as the junction of RAS-related signal pathways that play an important role in the development of prostate carcinogenesis. SOS1 is therefore also a key target for prostate cancer treatment. However, only one SOS1 small molecule inhibiting BI 1701963 has entered the clinical study stage so far, and both clinical trials of this small molecule inhibitor (NCT 04835714, NCT 04627142) have been declared to be terminated due to severe toxicity. To date, there are no available inhibitors for SOS1 on the market.
Combination therapy has been widely used for the treatment of complex diseases caused by abnormalities in various signaling pathways, often with better anti-tumor efficacy than single-target combination therapy. However, co-administration often suffers from the following problems: 1) Acute toxicity and delayed toxicity may be more likely to occur when administered in combination, particularly when less selective agents are used in combination; 2) Because the combined administration relates to a plurality of medicines, the proportion and the dosage of the medicines need to be considered, the administration mode is complex, and the compliance of patients is easy to be poor; 3) The combined administration can cause mutual interference of medicines in-vivo metabolism, and the pharmacokinetic properties of the medicines cannot be accurately predicted; 4) Adverse reactions caused by drug-drug interactions may occur in combination, and the pharmacodynamic characteristics of combination are difficult to predict accurately.
Disclosure of Invention
The invention aims to: the invention aims to provide SOS1 and EGFR double-target compounds with good curative effect and reduced drug resistance and toxicity, and a second aim of the invention is to provide a preparation method and application of the double-target compounds.
The technical scheme is as follows: the invention discloses an SOS1 and EGFR double-target compound or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structural formula shown in a formula (I):
the preparation method of the compound comprises the following steps:
(1) Adding the raw materials 1 and 2 into isopropanol, stirring and heating, vacuum concentrating, separating and purifying to obtain an intermediate 3;
(2) Dissolving the intermediate 3, the compound 4 and triphenylphosphine into dichloromethane, cooling, stirring and reacting, then dropwise adding diisopropyl azodicarboxylate, stirring and reacting at room temperature, concentrating in vacuum, separating and purifying to obtain a SOS1 and EGFR double-target compound;
the invention also provides a pharmaceutical composition, which is a preparation prepared from a double-target compound shown in the formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or auxiliary materials.
Preferably, the pharmaceutically acceptable carrier and/or adjuvant comprises diluents, binders, surfactants, wetting agents, lubricants, fillers, disintegrants, colorants, glidants, stabilizers, suspending agents, buffers, emulsifiers, granulating agents, anti-adherents, gelling agents, absorption retarders, dissolution inhibitors, enhancers, adsorbents, chelating agents, preservatives, colorants, flavoring agents, or sweeteners.
Preferably, the preparation is tablet, capsule, oral liquid, injection, lyophilized powder for injection, transdermal agent, aerosol, solid preparation, liposome, sustained and controlled release preparation, pill, suppository, granule, powder, nanometer preparation, syrup, medicated wine, tincture or distillate.
The compound or the stereoisomer or the pharmaceutically acceptable salt thereof, and the application of the pharmaceutical composition in preparing SOS1/EGFR double-target inhibitor drugs.
The use of the above compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the above pharmaceutical composition for the manufacture of a medicament for inhibiting the RAS signaling pathway.
The application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing tumors.
Further, the tumor includes prostate cancer, colon cancer, lung cancer, breast cancer, stomach cancer, esophageal cancer, cervical cancer, glioma, nasopharyngeal carcinoma, liver cancer, ovarian cancer or lymphoma.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: (1) SOS1 and EGFR double-target compounds can effectively inhibit cell proliferation and promote apoptosis, and have good in-vivo anti-tumor activity and no obvious toxic or side effect; (2) The double targets of SOS1 and EGFR can generate cytotoxicity on EGFR inhibitor drug-resistant cancer cells, and simultaneously reduce toxicity to normal tissues caused by widely inhibiting RAS channels, so that a synergistic anti-tumor effect is achieved.
Drawings
FIG. 1 is a diagram of SE-9 in example 1 1 H NMR spectrum;
FIG. 2 is a MS spectrum of SE-9 in example 1;
FIG. 3 is an HPLC chromatogram of SE-9 in example 1;
FIG. 4 shows the result of SE-9 inhibiting SOS1 in example 4;
FIG. 5 is a graph showing the results of SE-9 inhibition of EGFR in example 5;
FIG. 6 shows the results of SE-9 promoting apoptosis of PC-3 cells in example 6;
FIG. 7 shows the results of SE-9 inhibiting PC-3 cell proliferation in example 7;
FIG. 8 shows the results of SE-9 inhibiting PC-3 cell proliferation in example 7;
FIG. 9 is the effect of SE-9 on tumor growth in nude mice in example 8;
FIG. 10 shows the effect of SE-9 on the body weight and blood biochemical index of nude mice in example 8, showing the toxic side effects of SE-9 on nude mice.
Description of the embodiments
The technical scheme of the invention is further described below with reference to the accompanying drawings.
Example 1
Preparation of SOS1 and EGFR double-target compound SE-9
(1) 4-chloro-7-methoxyquinazolin-6-yl acetate (267 mg, 1 mmol) and(R)1- (3-fluorophenyl) ethylamine (418 mg, 3 mmol) was dissolved in isopropanol and the reaction mixture was stirred at 60℃for 8h, then concentrated in vacuo and the crude product purified on a silica gel column to give intermediate 3 (33%). 1 H NMR (400 MHz, DMSO)δ9.42 (s, 1H), 8.23 (s, 1H), 7.98 (d,J= 7.9 Hz, 1H), 7.71 (s, 1H), 7.37 – 7.31 (m,1H), 7.27 – 7.22 (m, 2H), 7.09 (s, 1H), 7.04 – 6.99 (m, 1H), 5.57 – 5.50 (m, 1H), 3.93 (s, 3H), 1.55 (d,J= 7.1 Hz, 3H)。
(2) Intermediate 3 (157 mg, 0.5 mmol) obtained in step (1), tetrahydro-2H-pyran-4-ol (61 mg,0.6 mmol) and triphenylphosphine (183 mg,0.6 mmol) were dissolved in dichloromethane; stirring the reaction mixture at 0 ℃ for reaction for 10 min; after that, diisopropyl azodicarboxylate (121 mg,0.6 mmol) was added dropwise to the mixture. Mixing the reactionStirring at room temperature for reaction 6h, and concentrating in vacuum; the crude product was purified on a silica gel column to give compound SE-9 (21%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 8.06 (d,J= 7.7 Hz, 1H), 7.87 (s, 1H), 7.67 – 7.51 (m, 1H), 7.42 – 7.30 (m, 1H), 7.29 – 7.18 (m, 2H), 7.12 (s, 1H), 7.09 – 6.97 (m, 1H), 5.59 (p,J= 7.6, 7.2 Hz, 1H), 4.72 (dt,J= 8.1, 4.1 Hz, 1H), 3.90 (s, 4H), 3.52 (t,J= 9.2 Hz, 2H), 2.03 (s, 1H), 2.00 (s, 1H), 1.67 (ddd,J= 12.7, 8.5, 3.9 Hz, 2H), 1.59 (d,J=7.0 Hz, 3H) (as in fig. 1); MS (ESI) M/z 398.2 [ M+H] + (as in figure 2); HPLC 99.024% (R) t = 10.080 min) (mobile phase a: meOH, B: H 2 O, ratio 70:30, column temperature: 40. DEG C, flow rate: 1mL/min, detector: 254 nm) (see fig. 3).
Example 2
Inhibition of SOS1 and EGFR by SE-9: SOS1 Single target inhibitor AXE and SE-9 Compounds were first dissolved in buffer (10 mM HEPES (pH 7.4), 5mM MgCl 2 150 mM NaCl, 1mM DTT, 0.0025% Igepal, 0.05% BSA) followed by SOS1 (40 nM, 2.5. Mu.L) and incubation at 25℃for 30 min. Then 2.5. Mu.L of buffer (80 nM KRAS) was added G12C 1 ng/. Mu.L of Mab Anti-6 His-XL665, 1 ng/. Mu.L of Mab Anti-GSH-Eu cryptat) and incubating the mixture at 25℃for 60 minutes. Homogeneous Time Resolved Fluorescence (HTRF) signals were recorded at an excitation wavelength of 320 nm to determine the inhibition of SOS1 by the compound. In addition, different concentrations of the EGFR single-target inhibitor gefitinib, SE-9 compound and EGFR kinase were added to the assay plate, followed by addition of the ATP-substrate mixture to initiate the enzymatic reaction. After 1 hour of reaction at room temperature, EDTA buffer was added to stop the reaction. Finally, the inhibition of EGFR by the compounds was determined by adding the detection solution to the assay plate and incubating 1 h. The results are shown in Table 1, SE-9 has obvious double inhibition effect on SOS1 and EGFR, and the inhibition effect is superior to that of SOS1 single-target inhibitor AXE and EGFR single-target inhibitor gefitinib.
Example 3
In vitro inhibition of tumor cells by SE-9: respectively administering different concentrations of TN-2 compound to human prostate cancer PC-3 cells, human colorectal adenocarcinoma DLD-1 cells, human liver cancer HepG2 cells, human chronic myelogenous leukemia K-562 cells and human lung cancer A549 cells, and placing at 37deg.C and 5% CO 2 For 72h, and determining the inhibition rate of the compound on tumor cells by using a tetramethyl azoazole (MTT) colorimetric method. As shown in Table 2, SE-9 has significant in vitro inhibitory activity against PC-3, DLD-1, hepG2, K-562 and A549 cells.
Example 4
Inhibition of cellular SOS1 Activity by SE-9: RAS-GTP levels were determined in PC-3 cells treated with different concentrations of SE-9 (0, 0.5, 12.5. Mu.M) and EGF was used as a positive control for SOS1 activation. As shown in FIG. 4, SE-9 was able to significantly reduce RAS-GTP levels in cells, whereas the positive control group had elevated RAS-GTP levels.
To further confirm the inhibition of SOS1 by SE-9, the levels of the RAS downstream effectors p-ERK and p-AKT were measured under the same conditions. As shown in FIG. 4, the changes in p-AKT and p-ERK levels were consistent with the changes in RAS-GTP, i.e., the decrease in p-AKT and p-ERK levels in SE-9 treated cells, and the positive control group had elevated p-AKT and p-ERK levels (A in FIG. 4 and B in FIG. 4). The results show that compound SE-9 mediated SOS1 inhibition can inhibit RAS signaling and result in a decrease in downstream effectors p-AKT and p-ERK.
Example 5
Inhibition of cellular EGFR activity by SE-9: PC-3 cells were treated with different concentrations of SE-9 (0, 0.5, 12.5. Mu.M) and Western blot analysis was performed. The results indicate that EGF, a positive activator for EGFR, significantly induces p-EGFR levels, whereas SE-9 treatment significantly attenuated this effect. Furthermore, SE-9 treatment significantly blocked EGF-mediated up-regulation of p-AKT levels compared to EGF alone treatment group, and the results in FIG. 5 indicate that SE-9 is a highly active EGFR inhibitor.
Example 6
Effect of SE-9 on apoptosis of PC-3 cell line: cells were treated with gradient concentration of SE-9 (0,0.5,2.5,12.5. Mu.M) and prepared in DMSO as a solvent, and after treatment, cells were double labeled with Annexin V-FITC and PI. A in FIG. 6 shows that SE-9 treatment can promote apoptosis of PC-3 cells. Further, as shown in B in FIG. 6 and C in FIG. 6, the apoptosis-detecting proteins suggest that SE-9 treatment can induce increased expression of the apoptosis proteins clear PARP and clear caspase 3, and the results indicate that SE-9 can promote apoptosis of PC-3 cells.
Example 7
The influence of SE-9 on the PC-3 cell colony forming ability is examined through a cell cloning experiment, and the independent viability of cells is expressed by the cell colony forming rate and the colony forming size, and the specific process is as follows: laying 500-800 cells/hole in 6-hole plate, culturing in 37 deg.C constant temperature incubator to adhere. After 48h, 2mL of fresh complete medium was changed, and different concentrations of SE-9 (0, 0.5,2.5, 12.5. Mu.M) were added, and the culture was continued in an incubator with DMSO as the solvent. The medium was then changed every 3 days. After 2 weeks, the supernatant was discarded, and after washing with PBS, pre-chilled methanol was added for 30 minutes. Then, PBS was added for washing, and 0.1% crystal violet staining solution was added for staining for 30 minutes. Finally, PBS is washed to the bottom of the pore plate to be transparent and colorless. Standing for several days, naturally drying, and photographing. As shown in FIG. 7, SE-9 can inhibit the clonogenic capacity and cell viability of PC-3 cell lines and is concentration dependent.
Cell proliferation potency was tested using EdU: cells were plated in 96-well plates at 1 w/well and placed in a 37℃incubator overnight to allow adherence. The next day 200. Mu.l of complete medium containing different concentrations of SE-9 (0, 0.5,2.5, 12.5. Mu.M) was changed, and the culture was continued in an incubator with DMSO as the solvent. After 24h of drug action, complete medium containing EdU reagent (10. Mu.M) was added and incubated at 37℃for 2h. PBS is added for 5min, 4% paraformaldehyde is added for 30min at room temperature for neutralization with 2mg/mL glycine for 5min, PBS is added for 5min, 0.5% Triton X-100 is added for permeation for 20min, and PBS is added for 5min. The reaction solution was incubated with kFluor488-azide at room temperature for 30min and washed with PBS for 5min. Incubation with 1 Xhoechst 33342 reaction solution at room temperature for 30min in dark place, PBS cleaning, and imaging under a fluorescence microscope, as shown in FIG. 8, edU proliferation test results also indicate that SE-9 treatment can inhibit cell proliferation activity, and that SE-9 can inhibit PC-3 cell proliferation.
Example 8
Effect of SE-9 on tumor growth in PC-3 cell ectopic engrafted tumor nude mice: adapting 6-8 week old BALB/C female nude mice to environment for about 1 week, digesting PC-3 cells with pancreatin, centrifuging at 1300rpm for 4min, adding 5mL fresh FBS-free DMEM, washing, counting, and adjusting concentration to 1×10 8 Each cell/ml was inoculated subcutaneously into mice at 100. Mu.L each. The tumor waiting volume is as long as 100mm 3 Administration was then started. Each cell was randomly divided into 3 groups of 6, each of which was SE-9 (5 mg/kg,20 mg/kg) dosing group, solvent blank. Intraperitoneal administration was performed on a group-by-group basis, 1 time every 4 days, and each mouse was given 100. Mu.L of drug (SE-9 in 4% DMSO+1% Tween-80+95% sterile PBS) or solvent blank (4% DMSO+1% Tween-80+95% sterile PBS) for 24 consecutive days. The body weight and tumor volume of the nude mice were recorded every 4 days during the experiment, and the growth of the nude mice was observed. Tumor tissue was taken at the end of the experiment, tumor weight was measured and inhibition ratio was calculated, inhibition ratio= (control tumor volume-dosing tumor volume/control tumor volume) ×100%. As shown by a in fig. 9 to E in fig. 9, the tumor volume of the SE-9-dosed group was dose-dependently reduced compared to the control group. In addition, the tumor weight was significantly lower in the SE-9-dosed group than in the control group (F in FIG. 9). Further, the measurement of G in FIG. 9 by TUNEL, CD31 and Ki67 reveals that SE-9 is capable of inducing apoptosis and inhibiting angiogenesis in vivo. Finally, fig. 10 shows that the body weight and blood biochemical indexes of the nude mice are detected, and the obtained results show that SE-9 has no obvious influence on the body weight of the nude mice and the biochemical indexes such as alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), hematuria (BUN), creatinine (CRE) and the like. These results indicate that SE-9 has good in vivo anti-tumor activity and no obvious toxic or side effects.

Claims (7)

1. A SOS1 and EGFR dual-target compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula shown in formula (I):
2. a process for the preparation of a compound as claimed in claim 1, comprising the steps of:
(1) Adding the raw materials 1 and 2 into isopropanol, stirring and heating, vacuum concentrating, separating and purifying to obtain an intermediate 3;
(2) Dissolving the intermediate 3, the compound 4 and triphenylphosphine into dichloromethane, cooling, stirring and reacting, then dropwise adding diisopropyl azodicarboxylate, stirring and reacting at room temperature, concentrating in vacuum, separating and purifying to obtain a SOS1 and EGFR double-target compound;
3. a pharmaceutical composition characterized by: the pharmaceutical composition is a preparation prepared from the double-target compound or the stereoisomer or the pharmaceutically acceptable salt thereof in claim 1 and one or more pharmaceutically acceptable carriers and/or auxiliary materials.
4. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3 for the preparation of a SOS1/EGFR dual-target inhibitor drug.
5. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for inhibiting the RAS signaling pathway.
6. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prophylaxis of tumors.
7. The use according to claim 6, wherein the tumour comprises prostate cancer, colon cancer, lung cancer, breast cancer, gastric cancer, oesophageal cancer, cervical cancer, glioma, nasopharyngeal carcinoma, liver cancer, ovarian cancer or lymphoma.
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