CN116570599B - Application of VS6766 in combination with LY3009120 and pharmaceutical composition - Google Patents
Application of VS6766 in combination with LY3009120 and pharmaceutical composition Download PDFInfo
- Publication number
- CN116570599B CN116570599B CN202310808712.5A CN202310808712A CN116570599B CN 116570599 B CN116570599 B CN 116570599B CN 202310808712 A CN202310808712 A CN 202310808712A CN 116570599 B CN116570599 B CN 116570599B
- Authority
- CN
- China
- Prior art keywords
- lxh254
- group
- raf
- kras
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- HHCBMISMPSAZBF-UHFFFAOYSA-N LY3009120 Chemical compound CC1=NC2=NC(NC)=NC=C2C=C1C1=CC(NC(=O)NCCC(C)(C)C)=C(F)C=C1C HHCBMISMPSAZBF-UHFFFAOYSA-N 0.000 title claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 77
- 206010009944 Colon cancer Diseases 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 30
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims 1
- UEPXBTCUIIGYCY-UHFFFAOYSA-N n-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-ylpyridin-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide Chemical compound C1=C(C=2C=C(N=C(OCCO)C=2)N2CCOCC2)C(C)=CC=C1NC(=O)C1=CC=NC(C(F)(F)F)=C1 UEPXBTCUIIGYCY-UHFFFAOYSA-N 0.000 abstract description 95
- 230000000694 effects Effects 0.000 abstract description 31
- 229940122056 RAF dimer inhibitor Drugs 0.000 abstract description 25
- 239000003112 inhibitor Substances 0.000 abstract description 24
- 208000005016 Intestinal Neoplasms Diseases 0.000 abstract description 19
- 201000002313 intestinal cancer Diseases 0.000 abstract description 14
- 102000043136 MAP kinase family Human genes 0.000 abstract description 11
- 108091054455 MAP kinase family Proteins 0.000 abstract description 11
- 230000035755 proliferation Effects 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 230000002195 synergetic effect Effects 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 67
- 229940079593 drug Drugs 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 102100030708 GTPase KRas Human genes 0.000 description 32
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 32
- YYACLQUDUDXAPA-MRXNPFEDSA-N (3r)-n-[3-[5-(2-cyclopropylpyrimidin-5-yl)-1h-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]-3-fluoropyrrolidine-1-sulfonamide Chemical compound C1[C@H](F)CCN1S(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=NC(=NC=2)C2CC2)=C1F YYACLQUDUDXAPA-MRXNPFEDSA-N 0.000 description 26
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 24
- 208000029742 colonic neoplasm Diseases 0.000 description 22
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 20
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 20
- 101150086096 Eif2ak3 gene Proteins 0.000 description 18
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 18
- 102200006531 rs121913529 Human genes 0.000 description 17
- 239000002609 medium Substances 0.000 description 16
- 102200006532 rs112445441 Human genes 0.000 description 15
- 238000001262 western blot Methods 0.000 description 12
- 230000037361 pathway Effects 0.000 description 10
- 239000000539 dimer Substances 0.000 description 9
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- 230000004663 cell proliferation Effects 0.000 description 7
- 238000001516 cell proliferation assay Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 7
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 6
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 6
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 6
- 238000010367 cloning Methods 0.000 description 6
- 101100523539 Mus musculus Raf1 gene Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000003698 anagen phase Effects 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- 206010069755 K-ras gene mutation Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000009702 cancer cell proliferation Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 101000771237 Homo sapiens Serine/threonine-protein kinase A-Raf Proteins 0.000 description 2
- 101150024075 Mapk1 gene Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 102100029437 Serine/threonine-protein kinase A-Raf Human genes 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000005757 colony formation Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 102200006539 rs121913529 Human genes 0.000 description 2
- 102200006538 rs121913530 Human genes 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 101150105104 Kras gene Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940125528 allosteric inhibitor Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003021 clonogenic effect Effects 0.000 description 1
- 238000010293 colony formation assay Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides application of VS6766 combined with LXH254 and a pharmaceutical composition, and relates to the technical field of biological medicine. Compared with the single use of the RAF/MEK double-target inhibitor VS6766 or the RAF dimer inhibitor LXH254, the combined use of the RAF/MEK double-target inhibitor VS6766 and the RAF dimer inhibitor LXH254 plays a synergistic effect on inhibiting the proliferation of KRAS mutant intestinal cancer cells, and can permanently and effectively inhibit the pMEK and pERK activities of MAPK channels, so that the combined use of the RAF/MEK double-target inhibitor VS6766 and the RAF dimer inhibitor LXH254 can not only adopt a combined use mode, but also can be prepared into pharmaceutical compositions or preparations for treating intestinal cancers, in particular KRAS mutant intestinal cancers, and has good application prospects.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to application of VS6766 combined with LXH254 in preparing a medicament for treating KRAS mutant colorectal cancer and a pharmaceutical composition.
Background
Colorectal cancer is the third most common cancer worldwide, 30-50% of colorectal cancers are associated with abnormal KRAS mutations, with very poor prognosis, but KRAS mutations have been a difficulty in tumor targeting drug development. KRAS mutations in colorectal cancer patients are most common with G12D (37%), G12V (30%), G13D (15%), other mutations such as G12C, etc. less than 10%, and only KRAS G12C inhibitors are currently available in bulk for the treatment of non-small cell lung cancer. It remains an urgent challenge to investigate targeted therapeutic strategies for KRAS mutant colorectal cancers.
Currently, inhibition of downstream MAPK (RAF-MEK-ERK) pathway signaling of the KRAS gene is an important strategy for indirectly blocking KRAS. Existing MAPK pathway inhibitors are mostly single-target, such as RAF or MEK inhibitors, have limited clinical benefit in colorectal cancer patients, and long-term administration always inevitably causes drug resistance, wherein most drug resistance mechanisms lead to reactivation of ERK signals, which highlights the strong dependence of KRAS mutant tumor cells on ERK signaling, thus how to achieve durable and effective inhibition of ERK signals is essential for the treatment of KRAS mutant colorectal cancer.
Disclosure of Invention
It is an object of the present application to provide the use of VS6766 in combination with LXH254 for the manufacture of a medicament for the treatment of KRAS mutated colorectal cancer.
The second object of the present application is to provide a pharmaceutical composition.
In order to achieve the above purpose, the present application provides the following technical solutions:
in a first aspect, the application provides the use of VS6766 in combination with LXH254 for the manufacture of a medicament for the treatment of KRAS mutated colorectal cancer.
In a second aspect, the application also provides a pharmaceutical composition comprising VS6766 and LXH254.
Based on the technical scheme, the application of the VS6766 combined LXH254 in preparing the medicine for treating KRAS mutant colorectal cancer and the medicine composition have at least the following beneficial technical effects:
compared with the single use of the RAF/MEK double-target inhibitor VS6766 or the RAF dimer inhibitor LXH254, the application of the RAF/MEK double-target inhibitor VS6766 and the RAF dimer inhibitor LXH254 in preparing medicaments for treating KRAS mutant colorectal cancer has the synergistic effect on inhibiting the proliferation of KRAS mutant intestinal cancer cells, and can permanently and effectively inhibit the activities of pMEK and pERK, so that the RAF/MEK double-target inhibitor VS6766 and the RAF dimer inhibitor LXH254 are combined in a mode of combined administration, and simultaneously, the medicament composition or the preparation is also prepared for treating the intestinal cancer, in particular the KRAS mutant intestinal cancer, and has good application prospect.
Drawings
In order to more clearly illustrate the embodiments of the application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a structural formula of VS6766 and LXH254, wherein FIG. 1a is a molecular structural formula of RAF/MEK dual-target inhibitor VS6766 and FIG. 1b is a molecular structural formula of RAF dimer inhibitor LXH254;
FIG. 2 is a graph showing the results of CCK8 cell proliferation experiments with VS6766 in combination with LXH254, wherein FIGS. 2a, 2b and 2c are graphs showing the results of CCK8 cell proliferation of colon cancer cells of HCT116-KRAS G13D at various concentrations in each drug group, respectively; FIGS. 2d, 2e and 2f are graphs showing the proliferation of colon cancer cells of SW480-KRAS G12V at different concentrations of CCK8 cells in each drug group;
FIG. 3 is a graph showing the synergy index of the results of CCK8 cell proliferation assay of VS6766 in combination with LXH254, wherein FIG. 3a is a graph showing the synergy index (CI) of the combination of VS6766 with LXH254 in CCK8 cell proliferation assay of colon cancer cells of HCT116-KRAS G13D, and FIG. 3b is a graph showing the synergy index (CI) of the combination of VS6766 with LXH254 in CCK8 cell proliferation assay of colon cancer cells of SW480-KRAS G12V;
FIG. 4 is a graph showing the results of a cloning experiment of VS6766 in combination with LXH254, wherein FIG. 4a is a graph showing the results of the number of cell clones of colon cancer cells of HCT116-KRAS G13D after each group of drug treatments, and FIG. 4b is a graph showing the results of the number of cell clones of colon cancer cells of SW480-KRAS G12V after each group of drug treatments;
FIG. 5 is a graph showing Western blotting results of VS6766 and LXH254, wherein FIG. 5a is a graph showing Western blotting results of colon cancer cells of HCT116-KRAS G13D after each group of drug treatment, and FIG. 5b is a graph showing Western blotting results of colon cancer cells of SW480-KRAS G12V after each group of drug treatment;
FIG. 6 is a graph showing the results of CCK8 cell proliferation experiments with VS6766 in combination with LXH254, LY3009120, HM95573 and PLX8394, wherein FIG. 6a is a graph showing the results of CCK8 cell proliferation of colon cancer cells of HCT116-KRAS G13D at various concentrations in each drug group; FIG. 6b is a graph showing the results of proliferation of SW480-KRAS G12V colon cancer cells at various concentrations of CCK8 cells in each drug group;
FIG. 7 is a graph showing experimental results of cloning of VS6766 in combination with LXH254, LY3009120, HM95573 and PLX8394, wherein 7a is a graph showing the results of cell clone numbers of colon cancer cells of HCT116-KRAS G13D after treatment with different drug groups, and FIG. 7b is a graph showing the results of cell clone numbers of colon cancer cells of SW480-KRAS G12V after treatment with different drugs;
fig. 8 is a graph showing western blotting results of VS6766 combined with LXH254, LY3009120, HM95573 and PLX8394, wherein fig. 8a is a graph showing western blotting results of colon cancer cells of HCT116-KRAS G13D and colon cancer cells of SW480-KRAS G12V after each group of drug treatments, and fig. 8b is a graph showing western blotting results of colon cancer cells of SW480-KRAS G12V after each group of drug treatments with increasing duration of drug action.
Detailed Description
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the application. All other embodiments, based on the examples herein, which are within the scope of the application as defined by the claims, will be within the scope of the application as defined by the claims.
The inventors found during the development process that: in KRAS mutant colorectal cancer cells, VS6766, the structural formula of which is shown in figure 1a, is a novel RAF/MEK double-target allosteric inhibitor, can be directly combined with MEK and form a stable RAF/MEK inhibitory complex, and can simultaneously inhibit activities of pMEK and pERK. Phase I clinical trials show that VS6766 is effective and safe for various KRAS mutant tumors, and the objective remission rate reaches 27%, and particularly has great therapeutic potential for KRAS G12V, G12D, G R mutant. And the half-life of the medicine is up to 55 hours, and the medicine effect and safety can be ensured simultaneously through an intermittent dosing scheme of twice a week, but the response time of most patients to VS6766 is about 6 months, and the medicine resistance still remains a bottleneck limiting the clinical application of the medicine.
RAF protein kinase is a key intermediate in MAPK pathway signaling, including ARAF, BRAF and CRAF, which are not functionally identical and can form homo-or heterodimers, and is an important node for activating downstream MEK-ERK pathway signaling. First generation BRAF V600E The monomer inhibitor has poor curative effect in colon cancer patients, and can only inhibit BRAF V600E Monomers, in turn, lead to strong activation of other monomers and dimers. A new generation of RAF dimer inhibitors: LXH254, LY3009120, HM95573 or PLX8394, all show efficacy in preclinical data, but drug resistance is always unavoidable. Due to the heterogeneity of different subtypes of RAF monomers and dimers, existing RAF dimer inhibitors are unable to fully inhibit the activity of all RAF dimers. For example LXH254, which has the structural formula shown in FIG. 1b, can effectively inhibit the signals of BRAF dimer and CRAF dimer, but has poor effect on ARAF dimer, and still causes ERK signal contradictionSexual activation.
In the treatment of KRAS mutant colorectal cancers, how to achieve a durable and effective inhibition of MAPK pathway signaling remains an important scientific issue. Based on the above, the application provides an application of a RAF/MEK double-target inhibitor VS6766 combined with a RAF dimer inhibitor LXH254 in preparing medicines for treating KRAS mutant colorectal cancer.
Example 1:
VS6766 in combination with LXH254 is effective in inhibiting proliferation and survival of KRAS mutant intestinal cancer cells.
1. The tumor cells and the medicaments are as follows:
KRAS mutated human colon cancer cells: HCT116 (KRAS G13D), SW480 (KRAS G12V) (national emphasis laboratory for biological treatment of the department of western medicine, university of si).
RAF/MEK dual-target inhibitors: VS6766 (Selleckchem, usa).
RAF dimer inhibitors: LXH254 (Selleckchem, usa).
2. The experimental method comprises the following steps:
experimental grouping:
(1) control group: cells were treated with DMSO (dimethyl sulfoxide, biofroxx, germany);
(2) VS6766 group: treatment of cells with VS6766 alone;
(3) LXH254 group: LXH254 treatment of cells alone;
(4) VS6766 in combination with LXH254 group: cells were treated simultaneously using VS6766 and LXH254. VS6766 and LXH254 were formulated in DMSO separately in solution and the cells were treated simultaneously with 2 solutions in combination.
(1) CCK8 cell proliferation assay:
fresh complete medium was prepared for cell culture: DMEM medium (Gibco, usa) +10% fetal bovine serum (Gibco, usa). The colon cancer cells HCT116 (KRAS G13D) and SW480 (KRAS G12V) in the logarithmic growth phase were collected and inoculated uniformly into 96-well plates (5000 cells/well, 100ul per well) with 3 replicate wells per drug concentration. And (3) placing the cells in an incubator at 37 ℃ overnight, and adding different drugs for treatment after the cells adhere to the walls.
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at concentrations of 0.5 μm, 1 μm and 2 μm, respectively;
(3) LXH254 group: LXH254 was added at concentrations of 1. Mu.M, 2. Mu.M and 4. Mu.M, respectively;
(4) VS6766+lxh254 group: the concentration of VS6766 and LXH254 was 0.5. Mu.M, or the concentration of VS6766 and LXH254 was 1. Mu.M, or the concentration of VS6766 and LXH254 was 2. Mu.M (molar ratio of VS6766 to LXH254 was 1:2).
Each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (100. Mu.L). After a further 72h of incubation, the medium was incubated with serum-free medium (DMEM) at a rate of 10:1 ratio dilute CCK8 reagent (Target Mol, USA), add 100ul diluted CCK8 reagent per well, after 0.5-4 hours of culture, the enzyme-labeled instrument measures 450nm absorbance, and calculate synergy index (CI) using Chou-Talalay formula, CI <1 indicates that both drugs have synergy.
(2) Cloning experiments:
colon cancer cells HCT116 (KRAS G13D) and SW480 (KRAS G12V) in logarithmic growth phase were inoculated uniformly into 12-well plates (1×10), respectively 4 cells/well), cells were attached and cultured for 3-4 days (4-5 small colonies were formed by individual cells).
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at a concentration of 1 μm;
(3) LXH254 group: LXH254 was added at 5 μm;
(4) VS6766+lxh254 group: VS6766 at a concentration of 1 μm and LXH254 at a concentration of 5 μm (molar ratio of VS6766 to LXH254 is 1:5) were added; each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (1 mL). The culture was continued for 5-10 days after the addition of the corresponding drug (2-3 changes of fresh complete medium and corresponding drug during the period). After colony formation, cells were prevented from being blown off by washing slowly 1 time with 0.01M PBS (Biosharp), fixed with paraformaldehyde for 20min, washed 1 time with PBS, stained with 0.5% crystal violet for 20min, washed 3 times with PBS, photographed, and the number of cell clones was observed.
(3) Western blot experiment:
cells SW480 and HCT116 in the logarithmic growth phase were inoculated uniformly into 6-well plates (5 wells per group to investigate the effect of drug treatment time on MAPK pathway) and treated with different drugs. The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at a concentration of 2 μm;
(3) LXH254 group: LXH254 was added at a concentration of 2. Mu.M;
(4) VS6766+lxh254 group: VS6766 at a concentration of 2 μm and LXH254 at a concentration of 2 μm (molar ratio of VS6766 to LXH254 is 1:1) were added; each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (2 mL).
After the corresponding drugs are added to each group, the treatment time of the drugs in 5 holes in each group is gradually increased in gradient, namely, the 5 holes are respectively cultured for 1 day (24 h), 2 days (48 h), 3 days (72 h), 4 days (96 h) and 5 days (120 h), and fresh complete culture medium and the corresponding drugs are replaced every 2-3 days to support cell growth and maintain the concentration of the drugs. Total cellular proteins were extracted at the corresponding time points, respectively, and Western blotting experiments were performed to examine the expression levels of MAPK pathway major proteins pMEK1/2 (S218/S222, abcam), pERK (Erk 1 (pT 202/pY 204) +Erk2 (pT 185/pY 187), abcam) and GAPDH (Santa Cruz).
Experimental results:
FIGS. 2 and 3 show the results of CCK8 cell proliferation assays with VS6766 in combination with LXH254. CCK8 is an experiment for detecting cell proliferation and cytotoxicity, indirectly reflecting the number of living cells through OD values. A synergy index (CI) may determine the synergy of two drugs, ci=1 for additive effects, CI >1 for antagonistic effects, CI <1 for synergistic effects, wherein: CI < 0.8-0.9 is low synergy, CI < 0.6-0.8 is medium synergy, CI < 0.4-0.6 is high synergy, CI < 0.2-0.4 is strong synergy. As can be seen from fig. 2: both the single-drug VS6766 group and the single-drug LXH254 group can effectively inhibit the proliferation of KRAS mutant intestinal cancer cells; the relative cell proliferation ratios of the VS6766+lxh254 groups were significantly lower than those of the single drug VS6766 and LXH254 groups, and as can be seen from fig. 3, the CI values of the VS6766+lxh254 groups were all less than 1, indicating that the use of VS6766 in combination with LXH254 has a synergistic effect on the treatment of KRAS mutated intestinal cancers. Still further, the CI index of both drugs was <0.6 (between 0.4 and 0.6), demonstrating the high synergy of VS6766 in combination with LXH254.
FIG. 4 is a graph showing the results of a cloning experiment in which VS6766 was combined with LXH254. The colony formation assay is used primarily to assess the ability of individual cells to survive, proliferate and form clones. As can be seen from fig. 4: both the single-drug VS6766 group and the single-drug LXH254 group can effectively inhibit the proliferation and survival of KRAS mutant intestinal cancer cells; whereas the number of clones of both cells in the VS6766+ LXH254 group was significantly less than in the single drug VS6766 group and the single drug LXH254 group. It is demonstrated that the combination of VS6766 and LXH254 is more effective in inhibiting KRAS mutant intestinal cancer cell proliferation and survival.
FIG. 5 is a graph showing the results of Western blotting experiments with VS6766 in combination with LXH254. KRAS promotes proliferation, differentiation of tumor cells by cascade phosphorylation of pMEK, pERK key kinases that activate MAPK pathways. The strong dependence of KRAS mutant tumor cells on ERK signaling, the durable and effective inhibition of ERK signaling is critical for the treatment of KRAS mutant intestinal cancers. As can be seen from fig. 5, short-time VS6766 single drug treatment was effective in inhibiting pMEK, pERK activity, whereas longer-time VS6766 single drug treatment had pMEK, pERK rebound activation; compared with a single VS6766 drug, the single LXH254 drug can permanently and effectively inhibit pMEK activity, but has weaker inhibition effect on pERK activity; while the VS6766+LXH254 group can permanently and simultaneously effectively inhibit pMEK and pERK activities, which is consistent with the results of CCK8 and clone formation experiments.
Therefore, the above results show that the combination of VS6766 and LXH254 has synergistic effect on inhibiting KRAS mutant intestinal cancer cell proliferation compared with the single use of VS6766 or LXH254, and can permanently and effectively inhibit activities of main kinases pMEK and pERK of MAPK pathway.
Example 2:
comparison of efficacy of synergistic antitumor effects of the RAF/MEK dual-target inhibitor VS6766 in combination with the RAF dimer inhibitors LXH254, LY3009120, HM95573 and PLX 8394.
1. The tumor cells and the medicaments are as follows:
KRAS mutated human colon cancer cells: HCT116 (KRAS G13D) and SW480 (KRAS G12V) (national emphasis laboratory for biological treatment, department of western medicine, university of si).
RAF/MEK dual-target inhibitors: VS6766 (Selleckchem, usa).
RAF dimer inhibitors: LXH254, LY3009120, HM95573 and PLX8394 (all available from Selleckchem, usa).
(1) LXH254: effectively inhibit kinase activity of BRAF and CRAF dimers;
(2) LY3009120: effectively inhibit kinase activity of BRAF and CRAF dimers;
(3) HM95573: effectively inhibit kinase activity of BRAF and CRAF dimers;
(4) PLX8394: the BRAF dimer is specifically isolated and its kinase activity is inhibited.
2. The experimental method comprises the following steps:
experimental grouping:
(1) control group: treating the cells with DMSO;
(2) VS6766 group: treatment of cells with VS6766 alone;
(3) RAF dimer inhibitor group: treating cells with a RAF dimer inhibitor alone;
(4) VS6766 in combination with RAF dimer inhibitor group: cells were treated simultaneously with VS6766 and RAF dimer inhibitor. The VS6766 and RAF dimer inhibitor were formulated in DMSO separately for use and the cells were treated simultaneously with 2 solutions in combination.
The experimental procedure is described in detail below.
(1) CCK8 cell proliferation assay:
fresh complete medium was prepared for cell culture: DMEM medium (Gibco, usa) +10% fetal bovine serum (Gibco, usa). The colon cancer cells HCT116 (KRAS G13D) and SW480 (KRAS G12V) in the logarithmic growth phase were collected and inoculated uniformly into 96-well plates (5000 cells/well, 100ul per well) with 3 replicate wells per drug concentration. And (3) placing the cells in an incubator at 37 ℃ overnight, and adding different drugs for treatment after the cells adhere to the walls.
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at concentrations of 0.1 μm, 0.5 μm and 1 μm, respectively;
(3) RAF dimer inhibitor group: LXH254, LY3009120, HM95573 or PLX8394 was added at a concentration of 2. Mu.M, respectively;
(4) VS6766+raf dimer inhibitor group: adding 0.1. Mu.M of VS6766 and 2. Mu.M of LXH254, LY3009120, HM95573 or PLX8394, or 0.5. Mu.M of VS6766 and 2. Mu.M of LXH254, LY3009120, HM95573 or PLX8394, or 1. Mu.M of VS6766 and 2. Mu.M of LXH254, LY3009120, HM95573 or PLX8394;
each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (100. Mu.L). After further incubation for 72h, CCK8 reagent (Target Mol, USA) was diluted in a 10:1 ratio with serum-free medium (DMEM), 100ul of diluted CCK8 reagent was added to each well, and after incubation for 0.5-4 h, absorbance at 450nm was measured by a microplate reader.
(2) Cloning experiments:
colon cancer cells in logarithmic growth phase, HCT116 (KRAS G13D) and SW480 (KRAS G12V), were inoculated uniformly in 12-well plates (1X 10) 4 cells/well), cells were attached and cultured for 3-4 days (4-5 small colonies were formed by individual cells).
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at a concentration of 1 μm;
(3) RAF dimer inhibitor group: LXH254, HM95573 or PLX8394 was added at a concentration of 5 μm; LY3009120 was added at a concentration of 1. Mu.M;
(4) VS6766+raf dimer inhibitor group: VS6766 at a concentration of 1 μm and LXH254, HM95573 or PLX8394 at a concentration of 5 μm were added; VS6766 at a concentration of 1. Mu.M and LY3009120 at a concentration of 1. Mu.M were added. Each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (1 mL). The culture was continued for 5-10 days after the addition of the corresponding drug (1 fresh complete medium and drug were changed every 2-3 days during the period). After colony formation, cells were prevented from being blown off by washing slowly 1 time with 0.01M PBS (Biosharp), fixed with paraformaldehyde for 20min, washed 1 time with PBS, stained with 0.5% crystal violet for 20min, washed 3 times with PBS, photographed, and the number of cell clones was observed.
(3) Western blot experiment:
(a) Effect of VS6766 in short time combination (24 h) with RAF dimer inhibitor.
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at a concentration of 0.1 μm;
(3) RAF dimer inhibitor group: LXH254, LY3009120, HM95573 or PLX8394 at a concentration of 2 μm was added;
(4) VS6766+raf dimer inhibitor group: VS6766 at a concentration of 0.1 μm and LXH254, LY3009120, HM95573 or PLX8394 at a concentration of 2 μm were added; each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (2 mL). And (5) adding the medicines, and then continuously culturing for 24 hours to extract the proteins.
(b) Effect of VS6766 in combination with RAF dimer inhibitor for prolonged periods (120 h).
The specific grouping is as follows:
(1) control group: adding DMSO;
(2) VS6766 group: VS6766 was added at a concentration of 1 μm;
(3) RAF dimer inhibitor group: LXH254, LY3009120, HM95573 or PLX8394 at a concentration of 2 μm was added;
(4) VS6766+raf dimer inhibitor group: VS6766 at a concentration of 1 μm and LXH254, LY3009120, HM95573 or PLX8394 at a concentration of 2 μm were added; each group of drugs was formulated with fresh complete medium and the final volume of the reaction system per well was the same (2 mL). After each group was added with the corresponding drug, the culture was continued for 120 hours, with fresh complete medium changed every 2-3 days to support cell growth and maintain drug concentration. Total cellular proteins were extracted at the respective time points, and Western blotting experiments were performed to detect the expression levels of MAPK pathway major proteins pMEK1/2 (S218/S222, abcam), pERK (Erk 1 (pT 202/pY 204) +Erk2 (pT 185/pY 187), abcam).
Experimental results:
FIG. 6 shows the results of CCK8 cell proliferation assays of VS6766 in combination with LXH254, LY3009120, HM95573 and PLX 8394. As can be seen from fig. 6a and 6b, LXH254 alone and LY3009120 alone inhibited KRAS mutant intestinal cancer cells HCT116-KRAS G13D or SW480-KRAS G12V more strongly than other RAF dimer inhibitors at the same concentration (2 μm). And the relative cell proliferation ratio of the VS6766+LXH254 group, the VS6766+LY3009120 group and the VS6766+HM95573 group is obviously lower than that of the single drug group, and the effect of the combination of the VS6766+PLX8394 group is poor compared with that of other combination groups. It was demonstrated that the use of VS6766 in combination with RAF dimer inhibitors (LXH 254, LY3009120 or HM 95573) had a synergistic effect on inhibiting proliferation of KRAS mutant intestinal cancers, whereas the use of VS6766 in combination with PLX8394 had poor efficacy.
FIG. 7 shows the results of a cloning experiment of VS6766 in combination with LXH254, LY3009120, HM95573 and PLX 8394. As can be seen from fig. 7: the single VS6766 can effectively inhibit the clone formation of KRAS mutant intestinal cancer cells, the single LXH254, the single LY3009120 and the single HM95573 can effectively inhibit the clone formation of KRAS mutant intestinal cancer cells, and the single PLX8394 has weaker inhibition effect; the number of clones of both cells in the VS6766+LXH254 group, the VS6766+LY3009120 group and the VS6766+HM95573 group was significantly less than that in the single drug group, while the combination of VS6766+PLX8394 had a poorer effect than the other combinations. It was demonstrated that VS6766 in combination with RAF dimer inhibitors (LXH 254, LY3009120 or HM 95573) more effectively inhibited KRAS mutant intestinal cancer cell proliferation and survival than alone, whereas VS6766 in combination with PLX8394 had poor efficacy.
FIG. 8 shows Western blot analysis of VS6766 in combination with LXH254, LY3009120, HM95573 and PLX8394 at a concentration of 2. Mu.M for each of the 4 RAF dimer inhibitors. As can be seen from fig. 8 a: the single VS6766 can effectively inhibit pERK activity and partially inhibit pMEK activity; the inhibition effect of each RAF dimer single drug on pMEK and pERK activity is weak; the VS6766+lxh254, VS6766+ly3009120, and VS6766+hm95573 groups inhibited pMEK, pERK more effectively than the VS6766 single and RAF dimer inhibitor single groups, whereas the VS6766+plx8394 combination group had less than the other combinations. As can be seen from FIG. 8b, the short-time (24 h) VS6766 single-drug treatment effectively inhibited pMEK and pERK activities, but the longer-time (120 h) VS6766 single-drug treatment had pMEK and pERK rebound activation; whereas the VS6766+LXH254, VS6766+LY3009120 and VS6766+HM95573 groups were both permanently effective in inhibiting pMEK and pERK activity, the combined VS6766+PLX8394 group was not as effective as the other groups, consistent with the results of the CCK8 and clonogenic experiments.
In conclusion, the combination of the VS6766 and the RAF dimer inhibitor (LXH 254, LY3009120, HM 95573) can effectively inhibit the proliferation and survival of KRAS mutant intestinal cancer cells, effectively inhibit the activities of key kinases pMEK and pERK of MAPK channels, and can reverse the rebound activation of pMEK and pERK caused by long-time single-drug treatment of the VS 6766. Of the above RAF dimer inhibitors, especially lxH254, LY3009120 and VS6766 have better combined effect, lxH254 shows more reliable effectiveness and safety in relevant clinical trials. Therefore, the combination of VS6766 and LXH254 has better therapeutic effect than other schemes and has more clinical transformation value.
The foregoing is merely illustrative of the present application, and the present application is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.
Claims (1)
- Use of vs6766 in combination with LY3009120 as the only active ingredient for the manufacture of a medicament for the treatment of KRAS mutated colorectal cancer, characterized in that the molar ratio of the VS6766 to the LY3009120 in the medicament is 1:1 or 1:2 or 1:4 or 1:20, wherein the structural formula of the VS6766 is。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310808712.5A CN116570599B (en) | 2023-07-04 | 2023-07-04 | Application of VS6766 in combination with LY3009120 and pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310808712.5A CN116570599B (en) | 2023-07-04 | 2023-07-04 | Application of VS6766 in combination with LY3009120 and pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116570599A CN116570599A (en) | 2023-08-11 |
| CN116570599B true CN116570599B (en) | 2023-10-20 |
Family
ID=87536083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310808712.5A Active CN116570599B (en) | 2023-07-04 | 2023-07-04 | Application of VS6766 in combination with LY3009120 and pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116570599B (en) |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016025648A1 (en) * | 2014-08-13 | 2016-02-18 | Celgene Avilomics Research, Inc. | Combinations of an erk inhibitor and a raf inhibitor and related methods |
| WO2019051296A1 (en) * | 2017-09-08 | 2019-03-14 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
| CN110022878A (en) * | 2016-11-03 | 2019-07-16 | 密执安大学评议会 | Small molecular double inhibitor of EGFR/PI3K and application thereof |
| CN110799245A (en) * | 2017-05-16 | 2020-02-14 | 生物医学谷探索股份有限公司 | Compositions and methods for treating cancers with atypical BRAF mutations |
| CN111868260A (en) * | 2017-08-07 | 2020-10-30 | 约翰斯霍普金斯大学 | Methods and materials for assessing and treating cancer |
| CN113498342A (en) * | 2018-12-21 | 2021-10-12 | 锐新医药公司 | Compounds involved in synergistic binding and uses thereof |
| WO2021214296A1 (en) * | 2020-04-24 | 2021-10-28 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Treatment of corona virus infections |
| CN115403583A (en) * | 2021-05-28 | 2022-11-29 | 四川大学 | Compound for targeted degradation of FAK protein and application thereof |
| WO2023056063A1 (en) * | 2021-10-01 | 2023-04-06 | Day One Biopharmaceuticals, Inc. | Raf kinase inhibitors for treating tumors harboring gene fusions |
| WO2023051685A1 (en) * | 2021-09-30 | 2023-04-06 | 北京大学 | Method for amplifying erythroid progenitors or erythroblasts, and application thereof |
| WO2023076991A1 (en) * | 2021-10-28 | 2023-05-04 | Verastem, Inc. | Combination therapy for treating abnormal cell growth |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018107146A1 (en) * | 2016-12-11 | 2018-06-14 | Memorial Sloan Kettering Cancer Center | Methods and compositions for treatment of braf mutant cancers |
| WO2020055760A1 (en) * | 2018-09-10 | 2020-03-19 | Mirati Therapeutics, Inc. | Combination therapies |
-
2023
- 2023-07-04 CN CN202310808712.5A patent/CN116570599B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016025648A1 (en) * | 2014-08-13 | 2016-02-18 | Celgene Avilomics Research, Inc. | Combinations of an erk inhibitor and a raf inhibitor and related methods |
| CN110022878A (en) * | 2016-11-03 | 2019-07-16 | 密执安大学评议会 | Small molecular double inhibitor of EGFR/PI3K and application thereof |
| CN110799245A (en) * | 2017-05-16 | 2020-02-14 | 生物医学谷探索股份有限公司 | Compositions and methods for treating cancers with atypical BRAF mutations |
| CN111868260A (en) * | 2017-08-07 | 2020-10-30 | 约翰斯霍普金斯大学 | Methods and materials for assessing and treating cancer |
| WO2019051296A1 (en) * | 2017-09-08 | 2019-03-14 | Genentech, Inc. | Diagnostic and therapeutic methods for cancer |
| CN113498342A (en) * | 2018-12-21 | 2021-10-12 | 锐新医药公司 | Compounds involved in synergistic binding and uses thereof |
| WO2021214296A1 (en) * | 2020-04-24 | 2021-10-28 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Treatment of corona virus infections |
| CN115403583A (en) * | 2021-05-28 | 2022-11-29 | 四川大学 | Compound for targeted degradation of FAK protein and application thereof |
| WO2023051685A1 (en) * | 2021-09-30 | 2023-04-06 | 北京大学 | Method for amplifying erythroid progenitors or erythroblasts, and application thereof |
| WO2023056063A1 (en) * | 2021-10-01 | 2023-04-06 | Day One Biopharmaceuticals, Inc. | Raf kinase inhibitors for treating tumors harboring gene fusions |
| WO2023076991A1 (en) * | 2021-10-28 | 2023-05-04 | Verastem, Inc. | Combination therapy for treating abnormal cell growth |
Non-Patent Citations (9)
| Title |
|---|
| Chong Zhang，等.A pan-RAF inhibitor LY3009120 inhibits necroptosis by preventing phosphorylation of RIPK1 and alleviates dextran sulfate sodium-induced colitis.Clin Sci (Lond) ..2019,第133卷(第08期),919-932. * |
| First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors;Maria Martinez-Garcia，等;Clin Cancer Res;第18卷(第17期);第4807页左栏倒数第5行至右栏第2行 * |
| Kras突变与肿瘤发生及治疗;李鹏飞;詹益红;祁苗;闫小慧;邵焕杰;;中国细胞生物学学报(第02期);第7-18页 * |
| LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors;Kelli-Ann Monaco，等;Clin Cancer Res;第27卷(第07期);第2067页图3 * |
| Marieke Lydia Kuijjer，等.Cancer subtype identification using somatic mutation data.Br J Cancer ..2018,第118卷(第11期),1492-1501. * |
| 宋彬彬 ; 张自阔 ; 朱庆枫 ; 何谷 ; 范举正 ; .MEK小分子抑制剂的设计、合成与初步活性研究.药学学报.2017,(第03期),81-89. * |
| 李雪梅 ; 杨林 ; .RAS基因突变型转移性结直肠癌的治疗研究进展.癌症进展.2019,(第11期),28-31. * |
| 樊新龙 ; 郭囡 ; 高鑫 ; 杨骁 ; 石岗 ; 赵月皎 ; .pan-RAF抑制剂LY3009120对分化型甲状腺癌细胞增殖、侵袭和迁移的影响及可能机制.现代肿瘤医学.2018,(第22期),35-38. * |
| 毛华杰.KIAA1143-TRIM58信号依赖泛素化修饰调控Rafs/ERK活性的分子机制研究.中国博士学位论文全文数据库 电子期刊 医药卫生科技辑.2023,(第02期),E072-24. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116570599A (en) | 2023-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ozkan-Dagliyan et al. | Low-dose vertical inhibition of the RAF-MEK-ERK cascade causes apoptotic death of KRAS mutant cancers | |
| Halaban et al. | PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells | |
| Estrada-Bernal et al. | MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways | |
| Lui et al. | Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: Inhibition of constitutive and interleukin 6–induced activation by iron depletion | |
| US20240009223A1 (en) | 6-thio-2'-deoxyguanosine (6-thio-dg) results in telomerase dependent telomere dysfunction and cell death in various models of therapy-resistant cancer cells | |
| Zhang et al. | A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG‑1 dependent on the liver cancer cell type | |
| Liu et al. | Long non-coding RNA-based glycolysis-targeted cancer therapy: feasibility, progression and limitations | |
| AU2020327537A1 (en) | New treatments involving miRNA-193a | |
| Pedini et al. | Joint action of miR‐126 and MAPK/PI3K inhibitors against metastatic melanoma | |
| Kotowski et al. | 3PO as a selective inhibitor of 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 in A375 human melanoma cells | |
| de Miguel et al. | Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer | |
| Lv et al. | Cancer cell-autonomous cGAS-STING response confers drug resistance | |
| Mulero‐Sánchez et al. | Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma | |
| CN116570599B (en) | Application of VS6766 in combination with LY3009120 and pharmaceutical composition | |
| CN112386593B (en) | Anti-tumor pharmaceutical composition containing sitagliptin and application thereof | |
| Li et al. | Inhibition of PTPN21 has antitumor effects in glioma by restraining the EGFR/PI3K/AKT pathway | |
| Onda et al. | Inhibition of VEGFR2 and EGFR signaling cooperatively suppresses the proliferation of oral squamous cell carcinoma | |
| CN116531389B (en) | Application of VS6766 combined with tripterine and pharmaceutical composition | |
| Wang et al. | S3I-201, a novel STAT3 inhibitor, inhibits growth of human soft tissue sarcoma cell lines | |
| CN116509868B (en) | Application of VS6766 combined with BAY293 and pharmaceutical composition | |
| CN107951888A (en) | The drug regimen and its application of Afatinib and 10-hydroxycamptothecine | |
| CN112933239A (en) | Application of reagent for activating endogenous PD-1 of tumor cells in preparation of antitumor drugs | |
| Gu et al. | Upregulation of CSNK1A1 induced by ITGB5 confers to hepatocellular carcinoma resistance to sorafenib in vivo by disrupting the EPS15/EGFR complex | |
| EP4110917A1 (en) | Mirna-193a for promoting immunogenic cell death | |
| CN106333951B (en) | A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |