CN110917199A - Application of small molecular compound in preparation of lung cancer chemotherapy sensitization medicine - Google Patents
Application of small molecular compound in preparation of lung cancer chemotherapy sensitization medicine Download PDFInfo
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- CN110917199A CN110917199A CN201911159454.2A CN201911159454A CN110917199A CN 110917199 A CN110917199 A CN 110917199A CN 201911159454 A CN201911159454 A CN 201911159454A CN 110917199 A CN110917199 A CN 110917199A
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- lung cancer
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- brivanib
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention creatively discovers the application of a small molecular compound in preparing a lung cancer chemotherapy sensitization medicine, discloses Brivanib as well as a screening method and a chemical structure thereof, and simultaneously discloses that Brivanib enhances the chemotherapy effect by specifically activating cGAS of a cGAS-cGAMP-STING signal pathway. Therefore, Brivanib provides a target spot for preparing a lung cancer chemotherapy sensitization medicine, the medicine can reduce the side effect of chemotherapy, and the life cycle of a tumor patient is prolonged while the life quality of the patient is improved.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of a small molecular compound in preparing a lung cancer chemotherapy sensitizing medicine.
Background
Lung cancer is the most common malignancy with the highest incidence and mortality worldwide, and most patients have been diagnosed in the middle and advanced stages, with a total five-year survival rate of only 15-30%. Chemotherapy is recommended as the first line treatment for lung cancer patients as the most sophisticated systemic treatment. However, the problem of chemotherapy resistance and the potential risk of inducing mutations leading to secondary tumors has been a major problem that has not been addressed for many years. Screening chemosensitizer is a hotspot which is widely regarded and researched for a long time, researchers try to design small molecular drugs for enhancing the curative effect of chemotherapeutics from various mechanisms, and progress is made, and the significant anti-tumor effect is proved in preclinical experiments, such as DMXAA, Amidobenzidazole (ABZI), JH-RE-06 and the like. However, these known small molecules have not been used for clinical transformation. Each small molecule drug is designed for one mechanism, and therefore, there is a self-adaptive population that does not cover all lung cancer patients. Therefore, the search for more chemosensitizing drugs with clinical transformation value is a key problem to be solved urgently in the field of tumor treatment.
Accumulation of foreign or self-DNA in the cytoplasm results in a strong immune response. The DNA receptor cGAS, which is called Cyclicguanosine monophosphate-adensonsine monophosphate synthsase, can sense cytoplasmic DNA, activate a downstream cGAS-cGAMP-STING signal pathway, cause the production of type I interferon and other proinflammatory cytokines, and further induce the activation of CD8+ T cells so as to cause tumor regression. The main action mechanism of the chemotherapeutic drug is just inhibiting the synthesis of normal DNA, and then leading to the accumulation of cytoplasmic DNA, further activating the cGAS-cGAMP-STING signal path and stimulating the anti-tumor immune response of the human body. Therefore, the screening of the small molecular drug capable of specifically activating the cGAS-cGAMP-STING has important clinical application value.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides the application of the small molecular compound in the preparation of the lung cancer chemosensitization drug, and experiments prove that the small molecular compound can specifically recognize cGAS and activate a cGAS-cGAMP-STING signal path, so that the antitumor immune response is amplified, and CD8 is induced+T cell activation leading to swellingTumor regression and prolongation of survival in tumor patients.
In order to achieve the purpose, the invention adopts the following technical scheme:
the first aspect of the invention provides an application of a small molecular compound in preparing a lung cancer chemotherapy sensitization medicine, wherein the small molecular compound is Brivanib, and the chemical structure is shown as the formula (I):
further, the lung cancer cell is an a549 lung cancer cell line.
The second aspect of the invention provides a medicament for enhancing the chemotherapy sensitivity of lung cancer, the effective component of the medicament is Brivanib, and the chemical structure is as shown in formula (I):
further, Brivanib enhances chemotherapy sensitivity by specifically recognizing cGAS and activating the cGAS-cGAMP-STING signaling pathway.
Further, Brivanib was screened by the following steps:
step one, sealing the isocyanate groups on the positions of the small molecules which are not spotted on the substrate by adopting BSA solution on the small molecule microarray containing the active compound;
step two, after sealing, adopting target protein cGAS with the volume of 1.5mL and the concentration of 10 mu g/mL to react with the small molecule microarray for 1 hour;
and step three, scanning, and then carrying out data acquisition and analysis.
The third aspect of the invention provides a medicament for up-regulating the expression level of lung cancer cell IFN- β, the effective component of the medicament is Brivanib, and the chemical structure is shown as formula (I):
by adopting the technical scheme, compared with the prior art, the invention has the beneficial effects that:
the invention provides application of a small molecular compound in preparing a lung cancer chemotherapy sensitization medicine, discloses Brivanib as the small molecular compound, a screening method and a chemical structure thereof, and simultaneously discloses that Brivanib enhances the chemotherapy effect by specifically activating cGAS of a cGAS-cGAMP-STING signal path. Therefore, Brivanib provides a target spot for preparing the lung cancer chemotherapy sensitizing drugs.
Drawings
FIG. 1 is an OI-RD difference image of a small molecule microarray after reaction with cGAS according to an embodiment of the present invention;
FIG. 2 is a difference image of the OI-RD image of the small molecule microarray in HEPES buffer solution after reaction with cGAS and the OI-RD image of the small molecule microarray in HEPES buffer solution before reaction in an embodiment of the present invention;
FIG. 3 is a difference image of the OI-RD image of the small molecule microarray of 1 in the protein solution after reaction with cGAS and the OI-RD image of the small molecule microarray of HEPES buffer solution before reaction in an embodiment of the present invention;
fig. 4 is a graph comparing the effect of specifically activating cGAS of 12 small molecules in one example of the present invention.
Detailed Description
The invention creatively discloses application of the screened small molecular compound in preparing a lung cancer chemotherapy sensitization medicine, and simultaneously discloses the effect of enhancing chemotherapy sensitivity of the small molecular compound by specifically activating cGAS.
The experimental contents of the application of the small molecule drug Brivanib in the tumor chemotherapy sensitivity mainly comprise the following aspects:
1. screening out small molecules specifically binding with the cGAS protein at high flux;
2. the small molecular drug Brivanib has an enhancement effect on the chemotherapy effect of tumors.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example one
The starting point and key step of novel drug research and development is the activity screening of compounds, and in the embodiment, small molecule compounds which specifically bind to cGAS protein are screened by a high-throughput screening method.
First, experiment method
1. On a micromolecule microarray containing 8500 active compounds, adopting 0.5mg/mL BSA solution to seal isocyanate groups at positions, on which micromolecules are not spotted, on a substrate, adopting a target protein cGAS with the volume of 1.5mL and the concentration of 10 mu g/mL to react with the micromolecule microarray for 1 hour, and taking an OI-RD difference image;
2. after washing the reacted small molecule microarray with HEPES buffer solution, two OI-RD images were taken successively in the buffer solution.
We performed 3 independent screens of cGAS, and out of 3 experiments at least 2 small molecules that became authentic positive spots were the final authentic positive compound positive spots.
Second, Experimental results and discussion
The adjacent double bright spots in fig. 1 represent small molecules that change after being filled with the target protein, including small molecules that can react with the target protein and small molecules that change in signal due to various reasons (regardless of the target protein cGAS). FIG. 2 is a difference image of the OI-RD image of the small molecule microarray in HEPES buffer solution after reaction and the OI-RD image of the small molecule microarray in HEPES buffer solution before reaction, where adjacent double bright spots include small molecules with slower dissociation rate that can react with cGAS and small molecules with signal changes due to various reasons.
The adjacent double bright spots appearing in fig. 1 but weakened or disappeared in fig. 2 correspond to small molecules that bind cGAS but have a faster dissociation rate, as shown in fig. 3 (see fig. 1-3 for details). Based on the above analysis, we obtained that the final positive compound of cGAS is Brivanib (an ATP-competitive inhibitor of VEGFR 2), whose chemical structural formula is shown in formula (i):
example two
The function of screening small molecules is verified at the cytology level.
First, experiment method
The A549 lung cancer cell strain is stimulated by exogenous ISD (cGAS activator) with the concentration of 10 mu M and cGAMP (STING activator) with the concentration of 10 mu M for 12h, small molecular compounds such as 19, 34, 42, 53, 54 and the like which are screened out are respectively added into the cell strain for parallel control, and then the IFN- β expression level of the tumor cells which are stimulated by different groups is detected by an RT-RCR technology.
Second, Experimental results and discussion
As shown in figure 4, compared with a control group, the small molecule 19 (Brivanib) can specifically enhance the expression level of IFN- β in A549 lung cancer cells stimulated by ISD but not enhance the expression level of IFN- β in A549 lung cancer cells stimulated by cGAMP, which indicates that Brivanib can specifically activate cGAS-STING pathway through cGAS and can up-regulate the expression of IFN- β in tumor cells.
According to the results, Brivanib can specifically recognize cGAS and activate cGAS-cGAMP-STING signal path, thereby amplifying anti-tumor immune response and inducing CD8+T cell activation leads to tumor regression and prolongs the survival of tumor patients. Therefore, Brivanib provides a target spot for preparing a lung cancer chemotherapy sensitization medicine, the medicine can reduce the side effect of chemotherapy, and the life cycle of a tumor patient is prolonged while the life quality of the patient is improved.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (6)
1. The application of the small molecular compound in preparing the lung cancer chemosensitization medicine is characterized in that the small molecular compound is Brivanib, and the chemical structure is shown as the formula (I):
2. the application of the small molecule compound in the preparation of the lung cancer chemosensitization medicine according to claim 1, wherein the lung cancer cell is an A549 lung cancer cell line.
3. The medicine for enhancing the chemotherapy sensitivity of the lung cancer is characterized in that the effective component of the medicine is Brivanib, and the chemical structure of the medicine is shown as the formula (I):
4. the drug for enhancing chemotherapy sensitivity of lung cancer according to claim 3, wherein Brivanib enhances chemotherapy sensitivity by specifically recognizing cGAS and activating the cGAS-cGAMP-STING signaling pathway.
5. The drug of claim 4, wherein Brivanib is selected by the following steps:
step one, sealing the isocyanate groups on the positions of the small molecules which are not spotted on the substrate by adopting BSA solution on the small molecule microarray containing the active compound;
step two, after isocyanate groups at positions of small molecules which are not spotted on the substrate are sealed, target protein cGAS with the volume of 1.5mL and the concentration of 10 mu g/mL is adopted to react with the small molecule microarray for 1 hour;
and step three, scanning the microarray, and then collecting and analyzing data.
6. A medicine for up-regulating lung cancer cell IFN- β expression level is characterized in that the effective component of the medicine is Brivanib, and the chemical structure of the medicine is shown as formula (I):
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113069447A (en) * | 2021-04-20 | 2021-07-06 | 上海市肺科医院 | Application of carvedilol in preparation of STING agonist and chemotherapy sensitization drugs |
Citations (2)
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| CN102307475A (en) * | 2009-02-04 | 2012-01-04 | 彼帕科学公司 | Treatment of lung cancer with a PARP inhibitor in combination with a growth factor inhibitor |
| CN107427003A (en) * | 2015-02-02 | 2017-12-01 | 梅制药公司 | Therapeutic alliance |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307475A (en) * | 2009-02-04 | 2012-01-04 | 彼帕科学公司 | Treatment of lung cancer with a PARP inhibitor in combination with a growth factor inhibitor |
| CN107427003A (en) * | 2015-02-02 | 2017-12-01 | 梅制药公司 | Therapeutic alliance |
Non-Patent Citations (5)
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| FRANCIS LEE等: "Synergistic activity of ixabepilone plus other anticancer agents", 《THER ADV MED ONCOL》 * |
| IVAN DIAZ-PADILLA和LILLIAN L SIU: "Brivanib alaninate for cancer", 《EXPERT OPIN. INVESTIG. DRUGS》 * |
| JAKUB HOFMAN等: "Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes", 《MOL. PHARMACEUTICS》 * |
| PUNIT H. MARATHE等: "Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate", 《CANCER CHEMOTHER PHARMACOL》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113069447A (en) * | 2021-04-20 | 2021-07-06 | 上海市肺科医院 | Application of carvedilol in preparation of STING agonist and chemotherapy sensitization drugs |
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