CN116570599A - Application of VS6766 combined with LXH254 and pharmaceutical composition - Google Patents
Application of VS6766 combined with LXH254 and pharmaceutical composition Download PDFInfo
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- 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 title claims abstract description 99
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- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 32
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- 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
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Classifications
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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
-
- 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
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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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- 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
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- 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, is effective in inhibiting the signals of BRAF dimer and CRAF dimer, but has poor effect on ARAF dimer, which still results in contradictory activation of ERK signal.
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 (2)
- Use of vs6766 in combination with LXH254 for the manufacture of a medicament for the treatment of KRAS mutated colorectal cancer.
- 2. A pharmaceutical composition comprising VS6766 and LXH254.
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