CN117756893A - EGFR (epidermal growth factor receptor) inhibition polypeptide compound and preparation method and application thereof - Google Patents
EGFR (epidermal growth factor receptor) inhibition polypeptide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an EGFR (epidermal growth factor receptor) inhibition polypeptide compound and a preparation method and application thereof, and belongs to the technical field of biological medicines. The EGFR inhibiting polypeptide compound is shown as a general formula I, wherein Xaa1 is-OH or-NH 2 or-His-His-His-His-His-His-OH or-His-His-His-His-NH 2 . The EGFR inhibition polypeptide compound provided by the invention has excellent EGFR affinity, can be combined with EGFR with high expression in tumor cells, promotes apoptosis of the tumor cells, inhibits proliferation and migration, has small toxicity to normal cells, and has specificitySelectivity. Therefore, the EGFR inhibition polypeptide compound and the pharmaceutically acceptable salt thereof can be potentially used for clinical treatment of anti-tumor and have wide development prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an EGFR (epidermal growth factor receptor) inhibition polypeptide compound and a preparation method and application thereof.
Background
Malignant tumors have become the second largest disease next to cardiovascular disease as a common and frequently occurring disease that severely threatens human health. Chemotherapy has become a major strategy for tumor therapy as a systemic tumor treatment tool. The root cause of the canceration of cells is gene mutation, and with the development of tumor biology and related subjects in recent years, the deep knowledge of the molecular mechanism of the development and prognosis of tumorigenesis is helpful for the cognition and clinical decision of targeted therapy. Among them, abnormal activation or inhibition of protein kinases including epidermal growth factor receptor (Epidermal growth factorreceptor, EGFR) is closely related to the occurrence and development of tumors, and inhibitors or agonists related to protein kinases are the mainstream choice for tumor targeting therapy. The development of safe and effective protein kinase-related inhibitors or agonists has become a hotspot in the development of current antitumor drugs.
EGFR is one of members of the EGFR family, and is widely distributed on cell membranes of various tissues of the human body, and is composed of an extracellular ligand binding region, a transmembrane region and an intracellular region. Under normal physiological conditions, EGFR is combined with a ligand thereof to induce EGFR intracellular tyrosine sites to be autophosphorylated and activated, so that functions of promoting cell proliferation, cell migration, cell invasion, angiogenesis and the like are exerted. However, in tumor cells, EGFR overexpression, mutation and abnormal activation can cause RTK autophosphorylation in intracellular areas, activate a series of downstream cascade signal transduction systems, such as RAS/RAF/MAPK, PI3K/AKT/mTOR, STAT and other transcription factors, and then cause continuous enhancement of RTK activity, cell phenotype transformation, promote occurrence and development of tumor tissues, and can effectively achieve the anti-tumor purpose by inhibiting EGFR activity. Therefore, the research uses EGFR as a target point, and the tumor molecule targeting drug for inhibiting EGFR activity has important clinical significance and wide application prospect.
Currently, targeted drugs against EGFR are mainly based on small molecule Tyrosine Kinase Inhibitors (TKIs) and monoclonal antibodies (mAbs). Of these, although the first to third generation TKIs have been widely used in the treatment of non-small cell lung cancer with EGFR activating mutations, most cancer patients carrying wild-type EGFR benefit only a limited amount relative to EGFR activating mutant patients. Meanwhile, EGFR-related mAbs have resulted in adaptability to different cancers due to site selectivity of binding to EGFR, and secondary drug resistance is very common. Thus, current anti-tumor drugs targeting EGFR remain a significant limitation in tumor, particularly metastatic tumor treatment. Numerous studies have shown that EGFR spatial distribution and stability are also key determinants regulating cancer progression, promoting EGFR degradation is a very potential alternative strategy to target EGFR-related cancers. In wild or mutant EGFR-driven tumors, EGFR degradation and recirculation disorders are present in many cases, which in turn lead to continued activation of downstream pathways that promote tumor progression. Thus, promoting EGFR degradation and inhibiting recycling is a hotspot in recent years of research targeting wild-type and mutant EGFR. However, no relevant report has been made on achieving the goal of promoting EGFR degradation and inhibiting recycling.
Disclosure of Invention
The EGFR inhibition polypeptide compound provided by the invention can obviously promote apoptosis, inhibit proliferation and migration of tumor cells, has low toxicity to normal cells and has good selectivity.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides an EGFR inhibition polypeptide compound and pharmaceutically acceptable salts thereof, wherein the EGFR inhibition polypeptide compound is shown as a general formula I; the general formula I: pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-Xaa1; wherein Xaa1 is-OH or-NH 2 or-His-His-His-His-His-His-OH or-His-His-His-His-NH 2 。
Preferably, the method comprises the steps of, xaa1 is-OH or-His-His-His-His-His-His-His-OH.
The invention provides a preparation method of an EGFR inhibition polypeptide compound, which comprises the steps of preparing a polypeptide-resin compound by adopting a microwave-promoted Fmoc/tBu orthogonal protection solid-phase synthesis method, cracking the polypeptide-resin compound by a cracking agent to obtain a crude product, and purifying the crude product to obtain the EGFR inhibition polypeptide compound.
Preferably, the solid phase synthesis method is used for preparing the polypeptide-resin complex by sequentially accessing the protective amino acid on the carrier resin through the solid phase coupling synthesis method.
The invention provides a pharmaceutical composition comprising the EGFR inhibiting polypeptide compound and/or a pharmaceutically acceptable salt of the EGFR inhibiting polypeptide compound.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Preferably, the dosage form of the pharmaceutical composition includes tablets, capsules, elixirs, syrups, troches, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories or compound preparations.
The invention provides an application of the EGFR inhibition polypeptide compound or the EGFR inhibition polypeptide compound obtained by the preparation method in preparing antitumor drugs.
The invention provides application of pharmaceutically acceptable salts of EGFR inhibition polypeptide compounds in preparation of antitumor drugs.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention provides a novel EGFR inhibition polypeptide compound which has excellent EGFR affinity, can be combined with EGFR with high expression in tumor cells, is combined in a ligand-dependent mode and induces Tyr1045 locus autophosphorylation of EGFR, recruits c-Cbl to promote ubiquitination degradation of EGFR so as to inhibit cyclic reuse of EGFR, promote apoptosis of tumor cells, inhibit proliferation and migration, has low normal cytotoxicity, has good selectivity, has the same effect on EGFR mutant EGFRvIII, and relieves the occurrence of secondary drug resistance to a certain extent. Therefore, the EGFR inhibition polypeptide and the pharmaceutically acceptable salt thereof can be potentially used for clinical treatment of tumor, and have wide development prospect.
(2) The invention utilizes microwave to promote solid phase synthesis of novel EGFR inhibition polypeptide, which greatly improves the coupling reaction rate. The conventional solid phase synthesis method is used for fully coupling an amino acid to the resin, usually 2-20 h or even longer is needed, and the average microwave time is only about 10 min; the conventional solid-phase synthesis method usually needs 30min to 1h for removing Fmoc protecting groups, and microwaves only need about 5min on average, so that the efficiency of polypeptide synthesis is greatly improved, and the synthesis period is shortened.
(3) The purity of the crude product of the novel EGFR inhibition polypeptide synthesized by utilizing the microwave-assisted solid phase is more than 80%, and is greatly improved compared with the conventional solid phase synthesis method, so that the subsequent purification work is facilitated.
(4) The novel EGFR inhibition polypeptide is synthesized by utilizing a microwave-assisted solid phase method, the cost is low, and the required protected amino acid is only required to be 2 times excessive on average due to higher coupling efficiency, and is greatly reduced by 4 to 5 times excessive compared with the conventional solid phase synthesis method. The method is easy to realize automation and large scale, which makes the method more suitable for industrial production.
Drawings
FIG. 1EGFR inhibiting polypeptide compound binds to EGFR and promotes its degradation results, wherein A: EGFR inhibition polypeptide compound 1 promotes the ubiquitination level of EGFR outcome, B: EGFR inhibiting polypeptide compound 2 binds EGFR and promotes its degradation results.
Fig. 2EGFR inhibiting polypeptide compound binds to egfrvlll and promotes its degradation results, wherein a: EGFR inhibition polypeptide compound 1 promotes the ubiquitination level outcome of EGFR; b: EGFR inhibiting polypeptide compound 2 binds EGFR and promotes its degradation results.
Detailed Description
The invention provides an EGFR inhibition polypeptide compound and pharmaceutically acceptable salts thereof, wherein the EGFR inhibition polypeptide compound is shown as a general formula I; the general formula I is Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-Xaa1, wherein Xaa1 is-OH or-NH 2 or-His-His-His-His-His-His-OH or-His-His-His-His-NH 2 . The polypeptide amino acid sequence in the EGFR inhibition polypeptide compound is Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu, and the amino acid abbreviated sequence is PSSPLGEWTDPALPLENQVWYHGAISRTDAENLL RLCKE (SEQ ID NO. 1).
In one embodiment of the present invention, the EGFR-inhibiting polypeptide compound is preferably Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-OH (EGFR-inhibiting polypeptide compound 1). The amino acid sequence of the polypeptide in the EGFR inhibiting polypeptide compound in this embodiment of the present invention is shown in SEQ ID NO. 1.
In another embodiment of the present invention, the EGFR inhibiting polypeptide compound is preferably Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-His-His-His-His-OH (EGFR inhibiting polypeptide compound 2). The polypeptide amino acid sequence in the EGFR inhibiting polypeptide compound of this embodiment of the present invention is Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-His-His-His-His, and the amino acid sequence is PSSPLGEWTDPALPLENQVWYHGAISRTDAENLLRLCKEHHHHHH (SEQ ID NO. 2).
The invention provides a preparation method of an EGFR inhibition polypeptide compound, which comprises the steps of preparing a polypeptide-resin compound by adopting a microwave-promoted Fmoc/tBu orthogonal protection solid-phase synthesis method, cracking the polypeptide-resin compound by a cracking agent to obtain a crude product, and purifying the crude product to obtain the EGFR inhibition polypeptide compound. The polypeptide-resin complex is prepared by the solid phase synthesis method, and protective amino acids are sequentially connected to carrier resin through the solid phase coupling synthesis method. Before the protected amino acid is accessed, the coupling efficiency of the resin is detected quantitatively by using an ninhydrin method or a bromophenol blue method, and the next coupling cycle can be accessed to the protected amino acid after the chromogenic reaction is negative.
The invention provides a pharmaceutical composition, which comprises the EGFR inhibition polypeptide compound and/or pharmaceutically acceptable salts of the EGFR inhibition polypeptide compound and also comprises a pharmaceutically acceptable carrier. The carriers of the present invention include, but are not limited to, one or more of binders, lubricants, disintegrants, dispersants, stabilizers, suspending agents, colorants, flavorants, buffers, solubilizing agents, and isotonic agents. Dosage forms of the pharmaceutical compositions of the present invention include, but are not limited to, tablets, capsules, elixirs, syrups, troches, inhalants, sprays, injections, films, patches, powders, granules, blocks, emulsions, suppositories, or compound preparations.
The invention also provides an application of the EGFR inhibition polypeptide compound and/or pharmaceutically acceptable salt thereof or the EGFR inhibition polypeptide compound obtained by the preparation method in preparing antitumor drugs. The tumor is selected from glioma, cervical cancer, colon cancer, lung adenocarcinoma, breast cancer or prostate cancer.
In the present invention, the chinese names corresponding to the english abbreviations referred to are shown in table 1:
table 1 english abbreviations and corresponding chinese names
In the present invention, all materials and reagents are commercially available products well known to those skilled in the art unless specified otherwise.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-OH (EGFR inhibiting polypeptide compound 1).
(1) Swelling of the resin: wang Resin50 mg (substitution 0.4 mmol/g) was weighed, swollen for 30min with 7mL DCM, suction filtered off of DCM, swollen for 30min with 10mL NMP, and finally rinsed clean with NMP, DCM, NMP 7mL, respectively.
(2) Microwave promotes removal of Fmoc protecting groups: placing the swelled resin into a reactor, adding 7mL of 25% piperidine/NMP (V/V) solution containing 0.1M HOBT, reacting for 1min in a microwave reactor with microwave power of 15W, controlling the reaction temperature within 50 ℃, using an air compressor to compress air for cooling, and filtering out the solution after the reaction is finished; 7mL of a 25% piperidine/NMP (V/V) solution containing 0.1M HOBT was added and reacted in a microwave reactor at a microwave power of 25W for another 4 minutes, the reaction temperature was controlled at 50℃and air-cooled using an air compressor. After the reaction was completed, the solution was filtered off and washed with NMP. The resin from which the initially attached Fmoc protecting groups were removed was obtained.
(3) Microwave-assisted synthesis of Fmoc-Glu (tBu) -Rink amide-MBHA Resin: fmoc-Glu (OtBu) -OH (0.04 mmol), HBTU (0.04 mmol), HOBT (0.04 mmol) and DIPEA (0.08 mmol) were dissolved in 10mLNMP, and the solution was added to the above resin and reacted in a microwave reactor at a microwave power of 25W for 7min at a reaction temperature of 50℃under compressed air cooling using an air compressor. After the reaction was completed, the reaction solution was filtered off, and the resin was washed 3 times with 7mL each of DCM and NMP.
(4) Detection of coupling efficiency: and (3) quantitatively detecting the coupling efficiency of the resin by using an ninhydrin method or a bromophenol blue method, and entering the next coupling cycle after the chromogenic reaction is negative.
Ninhydrin process: a small amount of resin particles are taken and washed by ethanol, put into a transparent small bottle, added with 5% ninhydrin, KCN pyridine solution (2 ml of 0.001M KCN is diluted in 98ml of pyridine) and 80% phenol ethanol solution for 2 drops each, heated at 100 ℃ for 5 minutes, and the resin is positive if the resin shows blue color.
Bromophenol blue process: a small amount of resin particles are taken and washed by diformylacetamide, and put into a transparent small bottle, 3 drops of 1% bromophenol blue dimethylacetamide solution are added, and the mixture is shaken for 3 minutes at normal temperature, and if the resin is blue, the positive result is obtained.
(5) Extension of peptide chain: according to the sequence of the peptide chains of the compound, the steps of deprotection and coupling are repeated from the C-end to the N-end to connect corresponding amino acids, and the coupling microwave promotes the reaction for 5-20 min to obtain the polypeptide-resin compound.
(6) Cleavage of polypeptide on resin: the polypeptide-resin complex obtained above was put into a reaction flask, and 10mL of a cleavage agent Reagent K (TFA/benzyl sulfide/water/phenol/EDT, 82.5:5:5:2.5, V/V) was added, followed by shaking at 0℃for 30min and then reaction at room temperature for 3h. After the reaction was completed, the mixture was filtered off with suction, washed three times with a small amount of TFA and DCM, and the filtrates were combined. Adding the filtrate into a large amount of glacial ethyl ether to separate out white flocculent precipitate, and freeze-centrifuging to obtain crude product of target polypeptide. Finally, 65.1mg of crude target compound was obtained in 94.5% yield.
(7) Purification of the polypeptide: the crude polypeptide was dissolved in 50% acetonitrile/water and purified using preparative liquid chromatography under the following conditions: c18 reverse phase column (320 mm. Times.28 mm,5 μm); mobile phase a:0.1% TFA/water (V/V), mobile phase B:0.1% TFA/acetonitrile (V/V); mobile phase gradient: 40% -90% of mobile phase B, 20min; the flow rate was 6mL/min and the detection wavelength was 214nm. The collected solution was lyophilized to obtain 30mg of pure product. The theoretical relative molecular mass is 4407.93.ESI-MS M/z found [ M+4H ]] 4+ 1102.94，[M+5H] 5+ 882.55，[M+6H] 6+ 735.63；calu[M+4H] 4+ 1102.98，[M+5H] 5+ 882.59，[M+6H] 6+ 735.66。
Example 2
Pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-His-His-His-His-His-His-His-OH (EGFR inhibiting polypeptide compound 2).
The novel EGFR inhibiting polypeptide compounds described in this example were synthesized according to the general method of example 1, based on the corresponding sequences, and their respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS). The theoretical relative molecular mass is 5230.79.ESI-MS M/z found [ M+4H ]] 4+ 1308.68，[M+5H] 5+ 1047.14，[M+6H] 6+ 872.78；calu[M+4H] 4+ 1308.70，[M+5H] 5+ 1047.16，[M+6H] 6+ 872.80。
Example 3 in vitro validation of anti-tumor Activity of EGFR inhibiting polypeptide Compounds
(1) The EGFR-inhibiting polypeptide compounds prepared in example 1 and example 2 have significant targeting affinity for EGFR and its mutant EGFRVIII
The compounds prepared above were tested for significant targeting affinity for EGFR using co-immunoprecipitation experiments: HEK293 cells were transfected with Ub-HA and GV141/Flag-EGFR and Ub-HA and GV141/Flag-EGFRvIII, respectively, by liposome transfection reagent, and 20uM of the above EGFR inhibitory polypeptide compound was added, treated for 24 hours, and then 10. Mu.M MG132 was added for 4 hours, and after collecting the proteins, anti-His-tag mAb-Magnetic Beads (purchased from MBL company, added for EGFR binding assay) or Anti-DDDDK-tag mAb-Magnetic Beads (purchased from MBL company, added for mutant EGFRVIII binding assay) were added, and after overnight at 4℃the proteins on the Beads were collected and the expression of each protein was detected by Westernblot. Wherein the Ub-HA, GV141/Flag-EGFR and GV141/Flag-EGFRvIII vectors are constructed by the following steps: linearizing the commercial GV219 vector and the commercial GV141 vector by using XhoI and KpnI, entrusting Shanghai Ji Kai gene chemistry technology to chemically synthesize Ub, EGFR and EGFRvIII gene sequences, respectively introducing XhoI and KpnI endonuclease sites at two ends of the sequences, connecting the synthesized Ub with the linearized GV219 vector, selecting recombinant clones, and carrying out enzyme digestion and sequencing identification to obtain the Ub-HA vector; and (3) connecting the synthesized EGFR and EGFRvIII gene sequences with a linearized GV141 vector, selecting recombinant clones, and performing enzyme digestion and sequencing identification to obtain GV141/Flag-EGFR and GV141/Flag-EGFRvIII vectors.
As shown in fig. 1 and 2, the EGFR inhibitor polypeptide compounds prepared in example 1 and example 2 have significant targeting affinity for both EGFR and its mutant egfrvlll, and can bind to EGFR and its mutant egfrvl and promote degradation thereof.
(2) In vitro anti-tumor Activity of EGFR inhibitory polypeptide Compounds prepared in example 1 and example 2
In vitro antitumor activity of the compounds of the examples was determined using an in vitro cell proliferation assay: taking human glioma cells U87, human cervical cancer HeLa, human colon cancer HCT116 and COLO320, human lung cancer A549 and NCIH2170, human breast cancer MDAMB231, human prostate cancer PC3, human gastric mucosa epithelial cells GES-1, human umbilical vein endothelial cells HUVEC, respectively with a ratio of 1×10 5 After incubation in 96-well plates at a density of/ml for 24h, the compounds of the examples were incubated for 48h with different concentration gradients. After the incubation, 20. Mu.l of CCK-8 solution was added to each well, after further incubation for 2 hours, the OD value at 450nm was measured by means of an ELISA reader, and finally the IC of the test compound was calculated by means of GraphPadprism 7.0 50 Values.
Table 2 in vitro cytotoxicity (IC) of the compounds of the examples 50 Value/. Mu. Mol.L -1 ) (one)
TABLE 3 in vitro cytotoxicity (IC) of the example compounds 50 Value/. Mu. Mol.L -1 ) (II)
As shown in tables 2 and 3, the compounds of the examples were significantly cytotoxic to EGFR-highly expressing tumor cells U87, hela, HCT116, A549, MDAMB231 and PC3 relative to normal cells GES-1, HUVEC and EGFR-lowly expressing tumor cells COLO320 and NCIH 2170. The EGFR inhibition polypeptide prepared in the embodiment 1-2 has good broad-spectrum anti-tumor activity, low toxicity to normal cells and good selectivity.
Example 4 in vivo validation of anti-tumor Activity of EGFR inhibiting polypeptide Compounds
The in vivo antitumor activity of the EGFR-inhibiting polypeptide compounds prepared in examples 1-2 was determined using a nude mouse tumor-bearing assay: u87 cells are respectively inoculated under the right armpit of a balb/c nude mouse until the tumor grows to 100mm 3 Animals were then randomly grouped into a control group and a dosing group, and were dosed intravenously 1 time every 2 days, and the EGFR inhibitor polypeptide compounds prepared in examples 1-2 were respectively injected intravenously, and the control group was injected intravenously with an equal volume of physiological saline, and after dosing, the body weight and tumor volume of the mice were measured daily, and the antitumor effect of the compounds was dynamically observed. After 6 doses, mice were sacrificed, tumor mass was surgically removed, weighed and relative tumor volume V (mm) was calculated 3 )。
TABLE 4U87 tumor volume in vivo (mm 3 )
Note that: * P.ltoreq.0.05 and p.ltoreq.0.01 are results of Student's t test against saline control group.
Table 5U87 in vivo tumor (g)
Note that: * p is less than or equal to 0.05 ** P.ltoreq.0.01 is the result of Student's t test against the physiological saline control group.
As shown in tables 4 and 5, the EGFR inhibitory polypeptide compounds prepared in examples 1-2 can effectively inhibit the growth of U87 in nude mice, and have good in vivo anti-tumor activity.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. An EGFR inhibition polypeptide compound and pharmaceutically acceptable salts thereof, wherein the EGFR inhibition polypeptide compound is shown in a general formula I;
general formula I: pro-Ser-Ser-Pro-Leu-Gly-Glu-Trp-Thr-Asp-Pro-Ala-Leu-Pro-Leu-Glu-Asn-Gln-Val-Trp-Tyr-His-Gly-Ala-Ile-Ser-Arg-Thr-Asp-Ala-Glu-Asn-Leu-Leu-Arg-Leu-Cys-Lys-Glu-Xaa1;
wherein Xaa1 is-OH or-NH 2 or-His-His-His-His-His-His-OH or-His-His-His-His-NH 2 。
2. The EGFR-inhibiting polypeptide compound of claim 1 and a pharmaceutically acceptable salt thereof, the method is characterized in that Xaa1 is-OH or-His-His-His-His-His-His-OH.
3. A method of making the EGFR inhibiting polypeptide compound of claim 1 or 2, wherein: preparing a polypeptide-resin compound by adopting a microwave-promoted Fmoc/tBu orthogonal protection solid-phase synthesis method, cracking the polypeptide-resin compound by a cracking agent to obtain a crude product, and purifying the crude product to obtain the EGFR inhibition polypeptide compound.
4. The method according to claim 3, wherein the solid phase synthesis method is a method of preparing the polypeptide-resin complex by sequentially attaching the protected amino acids to the carrier resin by solid phase coupling synthesis.
5. A pharmaceutical composition comprising the EGFR inhibitor polypeptide compound of claim 1 or 2 and/or a pharmaceutically acceptable salt of the EGFR inhibitor polypeptide compound.
6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 5, wherein the dosage form of the pharmaceutical composition comprises a tablet, capsule, elixir, syrup, lozenge, inhalant, spray, injection, film, patch, powder, granule, block, emulsion, suppository, or compound formulation.
8. Use of the EGFR inhibitor polypeptide compound according to claim 1 or 2 or the EGFR inhibitor polypeptide compound obtained by the method of preparation according to any one of claims 3 to 4 in the preparation of an antitumor drug.
9. The use of a pharmaceutically acceptable salt of an EGFR inhibitor polypeptide compound according to claim 1 or 2 in the manufacture of an antitumor medicament.
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