CN113941001B - Application of CRAF inhibitor in preparation of antitumor drugs - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
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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
- A61P35/02—Antineoplastic agents specific for leukemia
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides an application of a CRAF inhibitor in preparing an anti-tumor drug, belonging to the technical field of biological medicine. The CRAF inhibitor can inhibit the activation of the KIT and the downstream signal path thereof, provides a new direction for the treatment of KIT-related tumors, is beneficial to overcoming the clinical dilemma that the KIT-related tumors are resistant to the currently clinically applied KIT inhibitor and are intolerant to patients, and can be combined with the currently clinically applied KIT inhibitor to improve the treatment effect and optimize the prognosis curative effect of the patients.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a CRAF inhibitor in preparation of antitumor drugs.
Background
KIT is a type iii tyrosine kinase receptor, and its function-acquired mutation can cause various tumorigenesis, such as gastrointestinal stromal tumor, acute myeloid leukemia, mastocytosis, malignant melanoma, germ cell tumor, etc. Aiming at KIT mutation, currently, inhibitors Imatinib, sunitinib, regorafenib and Ripritinib are respectively used as one, two, three and four-wire targeted drugs for treating gastrointestinal stromal tumors, and good treatment effects are obtained, but a plurality of patients clinically have primary drug resistance to the KIT inhibitors or secondary drug resistance generated in the treatment process, so that the treatment of the KIT-related tumors fails. In addition, other KIT mutation-associated tumors such as mastocytosis and the like have not been currently available as KIT inhibitors for treatment.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of CRAF inhibitor in preparing antitumor drugs.
The invention provides application of a CRAF inhibitor in preparing an anti-tumor medicament.
The invention also provides application of the CRAF inhibitor combined with the KIT inhibitor in preparing antitumor drugs.
Preferably, the CRAF inhibitor comprises one or more of ZM336372, LY3009120, dabrafenib mesylate and GW 5074.
Preferably, the KIT inhibitor comprises one or more of imatinib, sunitinib, regorafenib and raptinib.
Preferably, the tumor comprises a tumor caused by a KIT mutation.
Preferably, the tumor comprises a tumor that is resistant to a KIT inhibitor.
Preferably, the tumor comprises a gastrointestinal stromal tumor, acute myeloid leukemia, mastocytosis, malignant melanoma, or germ cell tumor.
The invention also provides application of the CRAF inhibitor in preparing medicines for inhibiting KIT activation.
The invention also provides an antitumor drug, the active ingredients comprise a CRAF inhibitor and pharmaceutically acceptable auxiliary materials.
Preferably, the active ingredient further comprises a KIT inhibitor.
The invention provides application of a CRAF inhibitor in preparing an anti-tumor medicament. The signal pathways RAS/RAF/MEK/ERK and PI3K/AKT are key signal pathways of malignant tumors caused by KIT (III type tyrosine kinase receptor) mutation, and the CRAF inhibitor can inhibit the activation of MEK/ERK in the RAS/RAF/MEK/ERK signal pathway, directly inhibit the activation of KIT, and further inhibit the activation of other KIT downstream signal pathways (such as PI3K/AKT signal pathway). The inhibition of the activation of the KIT and the downstream signal channels by the CRAF inhibitor realizes the effective inhibition of the activation of the KIT through different mechanisms and can obviously inhibit the occurrence and development of KIT related tumor cells, so the invention provides a new treatment method for the treatment of KIT related tumors such as gastrointestinal stromal tumor, acute myeloid leukemia, mastocytosis, malignant melanoma, germ cell tumor and the like, and can help to overcome the drug resistance problem of KIT related tumors, especially gastrointestinal stromal tumor at present in treatment. In addition, the KIT inhibitor clinically used has side effects such as constipation, diarrhea, nausea, vomiting, myelosuppression and the like, and partial patients cannot be treated by adopting the medicines due to intolerance to the medicines, so that the invention provides a new choice for treating KIT-related tumors. Furthermore, since CRAF inhibitors inhibit KIT activation by different mechanisms, CRAF inhibitors may be used in combination with currently clinically used KIT inhibitors to enhance the therapeutic effect of KIT-associated tumors. The invention discovers that the combined action of the low-concentration KIT inhibitor and the low-concentration CRAF inhibitor has obviously better inhibition effect on tumor cells than that of any drug used singly, and the combined drug not only can reduce the use concentration of the drug and lighten the side effect on patients, but also can help the patients to obtain more outstanding treatment effect, and meanwhile, the synergistic anticancer effect caused by targeting different signal molecules can avoid or delay the occurrence of drug resistance.
Drawings
FIG. 1 shows the results of detection of KIT and its downstream signaling pathway activation by co-immunoprecipitation and western blot using ZM336372 for treatment of BaF3 cells expressing wild-type and mutant KIT;
FIG. 2 is a graph showing the results of treatment of BaF3 cells expressing wild-type and mutant KIT using LY3009120, detection of KIT and activation of its downstream signaling pathways by co-immunoprecipitation and western blot;
FIG. 3 is a graph showing the results of detection of KIT and activation of its downstream signaling pathways by co-immunoprecipitation and western blot using Dabrafenib Mesylate for treatment of BaF3 cells expressing wild-type and mutant KIT;
FIG. 4 is a graph showing the results of detection of KIT and activation of its downstream signaling pathways by co-immunoprecipitation and western blot using GW5074 for treatment of BaF3 cells expressing wild-type and mutant KIT;
FIG. 5 is a graph showing the results of detection of KIT and activation of its downstream signaling pathways by co-immunoprecipitation and western blot using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 for treatment of GIST-T1 cells expressing endogenous KIT mutations;
FIG. 6 is a graph showing the detection of KIT-mediated cell proliferation by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 to treat BaF3 cells expressing wild-type KIT;
FIG. 7 is a graph showing the detection of KIT-mediated cell proliferation by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 to treat BaF3 cells expressing the KIT/560D mutation;
FIG. 8 is a graph showing the detection of KIT-mediated cell proliferation by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 for treatment of BaF3 cells expressing the KIT/W557K558del mutation;
FIG. 9 is a graph showing detection of KIT-mediated cell proliferation by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 to treat GIST-T1 cells expressing endogenous KIT mutations;
FIG. 10 shows the results of detection of KIT and activation of its downstream signaling pathways by co-immunoprecipitation and western blot using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 for treatment of BaF3 cells expressing secondary mutant KIT;
FIG. 11 is a graph showing the results of KIT-mediated cell proliferation detected by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 for 48h in treatment of BaF3 cells expressing a secondary mutant KIT;
FIG. 12 is the results of KIT-mediated cell proliferation detected by CCK8 experiments using CRAF inhibitors ZM336372, LY3009120, dabrafenib Mesylate and GW5074 for 48h in GIST-T1 cells.
Detailed Description
The invention provides application of a CRAF inhibitor in preparing an anti-tumor medicament.
The invention also provides application of the CRAF inhibitor combined with the KIT inhibitor in preparing antitumor drugs.
In the present invention, the KIT inhibitor preferably includes one or more of Imatinib (Imatinib), sunitinib (Sunitinib), regorafenib (Regorafenib) and rapitinib (rispritinib). In the present invention, the Imatinib, sunitinib, regorafenib and Ripretinib sources are commercially available.
In the present invention, the CRAF inhibitor preferably comprises one or more of ZM336372, LY3009120, dabrafenib mesylate (Dabrafenib Mesylate) and GW 5074. In the present invention, the CRAF inhibitors are derived from conventional commercial sources. In the present invention, dabrafenib Mesylate is an ATP-competitive Raf inhibitor, and the IC50 for inhibiting C-Raf and B-RafV600E is 5nM and 0.6nM, respectively.
In the present invention, when the CRAF inhibitor is used in combination with the KIT inhibitor, the present invention is not particularly limited in terms of the ratio between the CRAF inhibitor and the KIT inhibitor.
In the present invention, the tumor preferably includes a tumor caused by KIT mutation. In the present invention, the tumor preferably includes a tumor that develops resistance to a KIT inhibitor. In the present invention, the tumor preferably includes gastrointestinal stromal tumor, acute myeloid leukemia, mastocytosis, malignant melanoma, or germ cell tumor.
The invention also provides application of the CRAF inhibitor in preparing medicines for inhibiting KIT activation.
The invention provides an anti-tumor medicament, which comprises an active ingredient including a CRAF inhibitor and pharmaceutically acceptable auxiliary materials. The dosage form of the medicament is not particularly limited, and conventional dosage forms in the field can be adopted. In the present invention, the auxiliary material is preferably physiological saline or glucose.
In the present invention, the active ingredient preferably further comprises a KIT inhibitor.
In the present invention, CRAF inhibitors are capable of inhibiting not only the activation of MEK/ERK in RAS/RAF/MEK/ERK signaling pathways, but also the activation of KIT directly, thereby inhibiting the activation of other KIT downstream signaling pathways (e.g., PI3K/AKT signaling pathways). Inhibition of the CRAF inhibitor on activation of the KIT and downstream signal channels thereof realizes effective inhibition of the KIT activation through different mechanisms, and can obviously inhibit occurrence and development of KIT related tumor cells. The clinical use of CRAF inhibitors helps to overcome the current problem of resistance to tumor therapy.
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.
EXAMPLE 1 inhibition of KIT and its downstream signalling by CRAF inhibitors
The plasmid pMSCVpfro-WT KIT with wild-type KIT (WT KIT) DNA is taken as a template, primers are designed to obtain common mutation KIT/V560D, KIT/W557K558del of gastrointestinal stromal tumor by a point mutation method, pMSCVpfuro-KIT/V560D and pMSCVpfuro-KIT/W557K 558del plasmids are obtained, the three plasmids are respectively incubated with Lipo2000 and then added to EcoPack cell culture medium respectively, ecoPack cells are transfected, virus supernatant is collected after 48 hours to infect BaF3 cells (BaF 3 cells do not express endogenous KIT), then 1.2 mu g/ml puromycin is used for screening for 2 weeks, and expression of KIT in BaF3 cells is detected by flow cytometry and westernblot to establish a BaF3 cell line stably expressing wild-type KIT (WT T), common mutation KIT/V560D, KIT/W557K558del of gastrointestinal stromal tumor. The three cell lines above and the gastrointestinal stromal tumor cell line GIST-T1 expressing the endogenous KIT mutations were then treated separately with different CRAF inhibitors (ZM 336372, LY3009120, dabrafenib mesylate and GW 5074), which were found to significantly inhibit activation of KIT and its downstream signaling pathways (RAS/RAF/MEK/ERK pathway and PI3K/AKT pathway) by co-immunoprecipitation and Western blot detection. The experimental results are shown in FIGS. 1 to 5. The experimental results show that as the concentration of CRAF inhibitor increases, the activation of KIT (pKIT) and its downstream pathways (pERK and pAKT) are both progressively reduced. Experimental results show that CRAF inhibitors significantly inhibit the activation of KIT and its downstream signaling pathways.
EXAMPLE 2 inhibition of CRAF inhibitors in KIT-associated tumor cell proliferation
BaF3 cells expressing wild-type KIT and W557K558del and V560D mutations and GIST-T1 cells expressing endogenous KIT mutations were treated with CRAF inhibitors, and KIT-mediated cell proliferation was examined by CCK8 assays to verify the effect of CRAF inhibitors on KIT-mediated cell proliferation. The results are shown in FIGS. 6 to 9. As a result, CRAF inhibitor is found to obviously inhibit cell proliferation, which shows that the inhibitor is expected to be used for treating KIT-related tumors.
EXAMPLE 3 CRAF inhibitors for treatment of drug resistant KIT-associated tumors
One of the main mechanisms of recurrence of gastrointestinal stromal tumors following Imatinib treatment is that the tumor acquires a new mutation (secondary mutation) on the basis of the primary KIT mutation (primary mutation), which secondary mutation results in Imatinib resistance in the patient, thereby reducing the patient's survival. We used pMSCVpmro-KIT/W557K 558del primary mutant plasmid as template, designed primer through point mutation method to get common V654A secondary mutation on the basis of W557K558del primary mutation, get pMSCVpmro-KIT/W557K 558del/V654A plasmid, incubating the plasmid with Lipo2000, then adding into EcoPack cell culture medium, transfecting EcoPack cells, collecting virus supernatant after 48h to infect BaF3 cells, then screening 2 weeks with 1.2 μg/ml puromycin, detecting KIT expression in BaF3 cells by flow cytometry and western blot to build BaF3 cell line stably expressing drug-resistant KIT secondary mutation. The above BaF3 cell lines were then treated with different CRAF inhibitors, which were found to significantly inhibit the activation of KIT and its downstream signaling pathways (RAS/RAF/MEK/ERK pathway and PI3K/AKT pathway) by co-immunoprecipitation and Western blot detection. The experimental results are shown in FIG. 10. The results show that as the concentration of CRAF inhibitor increases, the activation of KIT (pKIT) and its downstream pathways (pERK and pAKT) both gradually decrease. Experimental results show that CRAF inhibitor can obviously inhibit the activation of drug-resistant KIT and downstream signal channels thereof. .
Example 4
BaF3 cells expressing the KIT/W557K558del/V654A secondary mutation were treated with CRAF inhibitors, KIT-mediated cell proliferation was detected by CCK8 assay, and the effect of CRAF inhibitors on drug resistant KIT-associated tumor cell proliferation was detected. The results are shown in FIG. 11. As a result, the CRAF inhibitor can obviously inhibit the proliferation of drug-resistant tumor cells, which proves that the inhibitor is expected to be used for treating drug-resistant KIT related tumors.
Example 5
Effect of CRAF inhibitor and KIT inhibitor on KIT-related tumor cell proliferation
The present invention uses CRAF inhibitor in combination with KIT inhibitor Imatinib to treat GIST-T1 cells of gastrointestinal stromal tumor cell line, and detects KIT-mediated cell proliferation changes through CCK8 experiments. The results are shown in FIG. 12. The results show that the inhibition effect of the combined application of the low-concentration CRAF inhibitor and the low-concentration KIT inhibitor on the cell proliferation mediated by the KIT is obviously superior to that of the low-concentration KIT inhibitor alone or the low-concentration RAF inhibitor alone, which proves that the combined treatment of the CRAF inhibitor and the KIT inhibitor is beneficial to improving the treatment effect of KIT-related tumors.
Although the foregoing embodiments have been described in some, but not all, embodiments of the invention, according to which one can obtain other embodiments without inventiveness, these embodiments are all within the scope of the invention.
Claims (4)
- The use of a CRAF inhibitor in the manufacture of a medicament for combating gastrointestinal stromal tumors, wherein the CRAF inhibitor is one or more of ZM336372, dabrafenib mesylate and GW5074, and the gastrointestinal stromal tumor is an endogenous KIT mutated gastrointestinal stromal tumor.
- The use of a CRAF inhibitor in the manufacture of a medicament for combating gastrointestinal stromal tumors, wherein the CRAF inhibitor is one or more of ZM336372, dabrafenib mesylate and GW5074, and the gastrointestinal stromal tumor is a KIT secondary mutated gastrointestinal stromal tumor.
- The application of a CRAF inhibitor combined with a KIT inhibitor in preparing medicines for resisting gastrointestinal stromal tumor is characterized in that the CRAF inhibitor is one or more of ZM336372, dabrafenib mesylate and GW5074, and the KIT inhibitor is imatinib.
- 4. The use according to any one of claims 1 to 3, wherein the medicament further comprises pharmaceutically acceptable excipients.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105228983A (en) * | 2013-05-30 | 2016-01-06 | 普莱希科公司 | The compound regulated for kinases and indication thereof |
| CN106539777A (en) * | 2016-11-25 | 2017-03-29 | 佳木斯大学 | A kind of methanesulfonic acid Da Lafeini slow releasing tablet and preparation method thereof |
| CN111818915A (en) * | 2018-01-31 | 2020-10-23 | 德西费拉制药有限责任公司 | Combination therapy for treating gastrointestinal stromal tumors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105228983A (en) * | 2013-05-30 | 2016-01-06 | 普莱希科公司 | The compound regulated for kinases and indication thereof |
| CN106539777A (en) * | 2016-11-25 | 2017-03-29 | 佳木斯大学 | A kind of methanesulfonic acid Da Lafeini slow releasing tablet and preparation method thereof |
| CN111818915A (en) * | 2018-01-31 | 2020-10-23 | 德西费拉制药有限责任公司 | Combination therapy for treating gastrointestinal stromal tumors |
Non-Patent Citations (1)
| Title |
|---|
| Emerging Raf inhibitors;James A McCubrey等;《Expert Opinion on Emerging Drugs》;20091231;第14卷(第4期);第641页左栏第2段 * |
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