CN110063957A - Tarceva is preparing the purposes in FLT3 inhibitor class drug - Google Patents
Tarceva is preparing the purposes in FLT3 inhibitor class drug Download PDFInfo
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- CN110063957A CN110063957A CN201810065353.8A CN201810065353A CN110063957A CN 110063957 A CN110063957 A CN 110063957A CN 201810065353 A CN201810065353 A CN 201810065353A CN 110063957 A CN110063957 A CN 110063957A
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- flt3
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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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
The invention discloses Tarcevas to prepare the purposes in FLT3 inhibitor class drug.The invention also discloses purposes of the Tarceva in preparation treatment leukemia medicament.Tarceva of the present invention can inhibit the enzyme activity of FLT3, there is very strong inhibiting effect to FLT3-ITD saltant type leukaemia cell, and inhibit the function well of leukaemia in vivo, inhibition can be played the role of in the case where side effect very little, potential applicability in clinical practice is good.
Description
Technical field
The present invention relates to Tarcevas to prepare the purposes in FLT3 inhibitor class drug.
Background technique
Leukaemia is a kind of candidate stem cell malignant clone disease.Clonal leukaemia cell because proliferation out of control, point
Change obstacle, apoptosis mechanism largely proliferation accumulation in marrow and other hematopoietic tissues such as to be obstructed, and infiltrates other non-hematopoietic tissues
And organ, while inhibiting normal hematopoiesis function.Clinically often by leukaemia be divided into lymphocytic leukemia, myelocytic leukemia,
Cell mixing leukaemia etc..
Acute myelocytic leukemia (Acute myeloid leukemia, AML) is that medullary system hematopoietic stem/progenitor is pernicious
Disease.Using original and inmature marrow cell paraplasm in marrow and peripheral blood as main feature, clinical manifestation is anaemia, goes out
Blood, infection and fever, internal organs infiltration, metabolic disorder etc., the majority of cases state of an illness is suddenly heavy, and prognosis is dangerous, is such as not treated in time and often may be used
Threat to life.Acute Meyloid system leukaemia can be divided into M0~M7 and have 8 kinds altogether in clinic.According to statistics, the annual morbidity of China AML is about
It is 1.62/10 ten thousand, and shows an increasing trend year by year.However according to current understanding, the definite cause of disease of leukaemia is still not clear.
FLT3 kinases belongs to III receptor family tyrosine kinase member.Under normal circumstances, FLT3 is activated by its ligand FL,
And then activate a plurality of downstream signaling proteins, such as STAT5, MAPK, PI3K, NPM1, finally to the Proliferation, Differentiation of bone marrow cell at
Ripe performance adjustment effect.However, clinical research is found, in the tumour cell of about 1/3 acute myeloid leukaemia (AML) patient
Sustained activation mutation has occurred in FTL3, wherein occurs most being exactly that FLT3-ITD is mutated.Clinical research proves have
The patient of FLT3-ITD mutation is more worse than wild type FLT3 positive patient clinical prognosis, and the tumour cell of FLT3-ITD mutation
Insensitive to conventional medicament is to generate drug resistance and one of the main reason for leukemia relapse.Therefore, FLT3 is in acute myelogenous white blood
Key player is play in the occurrence and development of disease, is the important target for treating this kind of disease.
Tarceva (Erlotinib) is a kind of effective and orally available EGF-R ELISA (EGFR) tyrosine
Kinase inhibitor selectively and reversibly inhibits the autophosphorylation of intracellular EGFR related tyrosine kinases.Its structural formula is such as
Under.Prove that Tarceva can be used for the office of two or more chemotherapy regimens failure based on one III phase clinical research of foreign countries
Three lines of the non-small cell lung cancer of portion's advanced stage or transfer are treated.In addition, being used in combination with gemcitabine, Pancreas cancer patients can be extended
Life cycle.
Currently, having no that Tarceva inhibits FLT3 enzyme activity or the report for treating leukaemia.
Summary of the invention
The purpose of the present invention is to provide Tarcevas to prepare the purposes in FLT3 inhibitor class drug, to reduce FLT3
Enzyme activity, for treating leukaemia.
Present invention firstly provides Tarcevas to prepare the purposes in FLT3 inhibitor class drug.
FLT3 (Fms-like Tyrosine Kinase-3, fms- sample tyrosine kinase -3) is type III receptor tyrosine
Kinase families member.
FLT3 inhibitor: inhibit the substance of FLT3 enzyme activity.
The present invention also provides purposes of the Tarceva in preparation treatment leukemia medicament.
Further, the drug is prevention and/or treats because FLT3 high is expressed or activates the medicine of the related disease induced
Object.
Further, the drug is the drug for inhibiting FLT3 enzyme activity.
Further, the drug is prevention and/or treatment myelodysplastic syndrome, ocular neovascular or leukaemia
Drug.
Ocular neovascular refers to the new vessels of eye, including retinal neovascularization, choroidal neovascularization, cornea are new
Angiogenic etc..
Further, the drug is the drug of prevention and/or treatment acute myeloid leukaemia.
Further, the drug is the drug of prevention and/or treatment FLT3-ITD saltant type acute myeloid leukaemia.
Further, the drug be using Tarceva as active constituent, in addition pharmaceutically acceptable auxiliary material preparation and
At preparation.
The present invention also provides a kind of drugs for treating FLT3-ITD saltant type leukaemia, it is with Tarceva for activity
Ingredient, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Tarceva can inhibit the enzyme activity of FLT3, be a kind of FLT3 inhibitor, to FLT3-ITD saltant type leukaemia cell
Have very strong inhibiting effect, and in vivo inhibit leukaemia function well, can be in the case where side effect very little from
To the effect of inhibition, potential applicability in clinical practice is good.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is Tarceva in the embodiment of the present invention 1 on the active influence of FLT3 enzyme level.
Fig. 2 is the active influence of Tarceva FLT3 intracellular on MV4-11 in the embodiment of the present invention 2.
Fig. 3 is influence of the Tarceva to the activity in vivo of MV4-11 cell in the embodiment of the present invention 4.
Specific embodiment
Embodiment 1, Tarceva are to the enzyme level inhibitory activity of FLT3 kinases
1, experimental material
Liquid device, 384 plates, multiple labeling micropore board detector (Perkin Elmer),KinEASETM, FMS sample
Tyrosine kinase 3 (FLT3), be purchased from Beijing Yi Qiao divine boat.
2, experimental method
According to the optimization procedure operation provided in HTRF kit, the data of experiment are carried out by Graphpad software for experiment
Fitting.
3, experimental result
It will be seen from figure 1 that Tarceva shows significant inhibiting effect to FLT3 in enzyme level active testing,
Show that the drug can be by inhibiting the activity of FLT3 to generate corresponding drug action.
The active inhibition of embodiment 2, Tarceva FLT3 intracellular to MV4-11
1 experimental material
1.1 main agents
IMDM culture medium, fetal calf serum, pancreatin are purchased from Gibco company (Life technologies
corporation)。
FLT3 and p-FLT3 antibody is purchased from cell signaling technology company.
1.2 cell strain
MV4-11 cell strain is purchased from ATCC company, the U.S..
2 experimental methods
After the Tarceva (20,10,5,2.5 μM) of gradient concentration acts on MV4-11 cell 20h, by being collected by centrifugation
Cell, RIPA cracking, to extract intracellular total protein.Then, albumen is divided through SDS-PAGE electrophoretic separation and pvdf membrane transfer
From and be transferred on pvdf membrane.Then, it is combined respectively through FBS closing and FLT3 or p-FLT3 antibody mediated immunity and secondary antibody is hatched.
Finally, through ECL color developing detection various concentration Tarceva FLT3 protein expression intracellular on MV4-11 and active influence.
3, experimental result
Figure it is seen that Tarceva can effectively inhibit the phosphorylation of the intracellular FLT3 albumen of MV4-11, and it is right
The expression of FLT3 albumen does not show significantly to influence.Therefore, which generates anti-FLT3-ITD saltant type leukaemia effect master
To be derived from its inhibiting effect to intracellular FLT3.
Embodiment 3, the extracorporeal anti-tumor cell proliferation experiment of Tarceva
1 experimental material
1.1 main agents
RPMI-1640 and IMDM culture medium, fetal calf serum, pancreatin are purchased from Gibco company (Life technologies
corporation)。
Dimethyl sulfoxide (DMSO), tetramethyl azo azoles salt (MTT) are purchased from Sigma company (USA).
Tarceva is purchased from Nanjing Kang Manlin scientific & technical corporation, is configured to 20mg/ml storage with 100%DMSO when experiment in vitro
Liquid sets -20 DEG C of refrigerators and is kept in dark place spare, and facing the used time with complete culture solution is diluted to required concentration.
1.2 cell lines and culture
MV4-11 cell strain, MOLM-13 cell strain, IL3 dependent form pro-B lymphocyte Ba/F3 are purchased from U.S. ATCC public affairs
Department, the Ba/F3-FLT3-ITD cell for expressing FLT3-ITD albumen are presented by Sichuan University professor Yang Shengyong.The above cell strain is used
Containing 10% fetal calf serum, 100U/ml penicillin, 100 μ g/ml streptomysins RPMI-1640 or IMDM culture medium in 5%CO2、
It is cultivated under the conditions of 37 DEG C.
2 experimental methods
MOLM-13 cell is cultivated using the RPMI-1640 containing FBS, antibiotic；Using containing FBS, antibiotic
IMDM culture medium cultivates MV4-11 cell；Using the RPMI-1640 for containing FBS, antibiotic or corresponding cell factor (IL3)
Ba/F3-FLT3-ITD cell is cultivated.When cell grows to logarithmic growth phase, cell is collected by it according to 4000-
The amount of 15000 cells/wells is inoculated into 96 orifice plates.After for 24 hours, by the Tarceva of gradient concentration (20,10,5,2.5,1.25,
0.625,0.3125 μ g/mL) it is added in culture medium, it is placed in cell incubator and cultivates.After 72 hours, it is added 5mg/ml's
MTT sterile solution, and tri- liquid of SDS is added after effect 2-4 hours and stays overnight.Finally, detecting each well pair using microplate reader
The absorbance value of 570nm light beam, and calculate inhibiting rate using corresponding calculation formula and count Tarceva to the half of each cell
Number inhibition concentration, each Data duplication three times, and calculate average value.
3 experimental results
Proliferation inhibition activity of 1 Tarceva of table to various cell strains
As can be seen from Table 1, Tarceva is acute myelogenous to MV4-11, MOLM-13 being mutated with FLT3-ITD etc. white
Blood disease cell line has significant inhibitory activity, the μ of IC50 < 2 g/ml.Tarceva is to wild type Ba/F3 cell unrestraint activity
(μ of IC50 > 20 g/ml), and there is good selection to the Ba/F3-FLT3-ITD cell of the FLT3-ITD dependence of building growth
Property inhibitory activity.Therefore, Tarceva has targeted inhibition effect to FLT3-ITD saltant type acute myeloid leukemia cells in children.
Anti-tumor activity is tested in embodiment 4, Tarceva body
1 experimental material
1.1 main agents
IMDM culture medium, fetal calf serum, pancreatin are purchased from Gibco company (Life technologies
corporation)。
1.2 cell strain
MV4-11 cell strain is purchased from ATCC company, the U.S..
1.3 experimental animal
NOD-SCID mouse is purchased from BeiJing, China's consonance Experimental Animal Center.
2 experimental methods
Using 6~8 week old NOD-SCID mouse, according to about 7.5 × 106The concentration of a/0.1ml/ MV4-11 cell connects
In mouse, subcutaneously rear flank constructs acute myeloid leukaemia tumor model to kind, grows to 150-300mm to tumour3(about 15 days) afterwards,
Mice group (n=6) simultaneously starts to be administered orally.
Experimental group: drug solvent control group (5%DMSO+20%PEG400+75% water)；Tarceva 100mg/
Kgq.d. it is administered orally；Tarceva 50mg/kg q.d. oral administration；Tarceva 25mg/kg q.d. oral administration；Shu Ni
Positive control is used as Buddhist nun 10mg/kg q.d. oral administration.
Observation index: an every 3 days mouse weights of measurement and tumour major diameter, minor axis and calculate gross tumor volume (length ×
width2× 0.5) reactions such as, whether there is or not diarrhea for observation, twitch, fash, and weight is substantially reduced.
3 experimental results
From figure 3, it can be seen that Tarceva has hFL T3-ITD saltant type acute myeloid leukemia cells in children strain MV4-11
There is apparent tumor growth inhibiting effect, under 25,50,100mg/kg/d dosage, can obviously inhibit tumour growth, and be in
Dose-dependence.Do not find in administration process but that phenomena such as fash, diarrhea, death occurs in animal.
The experiment results show that Tarceva of the present invention is administered in the case where relatively low-dose, it can effectively inhibit leukaemia
Tumour, and side effect is smaller.
To sum up, Tarceva can inhibit the enzyme activity of FLT3, be a kind of FLT3 inhibitor, to FLT3-ITD saltant type leukaemia
Cell has very strong inhibiting effect, and inhibits the function well of leukaemia in vivo, can be the side effect very little the case where
Under play the role of inhibition, potential applicability in clinical practice is good.
Claims (9)
1. Tarceva is preparing the purposes in FLT3 inhibitor class drug.
2. purposes of the Tarceva in preparation treatment leukemia medicament.
3. purposes according to claim 1, it is characterised in that: the drug is prevention and/or treats because FLT3 high is expressed
Or the drug of the related disease of activation induction.
4. purposes according to claim 1 or 3, it is characterised in that: the drug is the drug for inhibiting FLT3 enzyme activity.
5. purposes according to claim 3 or 4, it is characterised in that: the drug is that prevention and/or treatment myelosis are different
The drug of normal syndrome, ocular neovascular or leukaemia.
6. purposes according to claim 1-5, it is characterised in that: the drug is prevention and/or treats acute
The drug of myelogenous leukemia.
7. purposes according to claim 6, it is characterised in that: the drug is prevention and/or treatment FLT3-ITD mutation
The drug of type acute myeloid leukaemia.
8. purposes according to claim 1-7, it is characterised in that: the drug be with Tarceva for activity at
Point, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
9. a kind of drug for treating FLT3-ITD saltant type leukaemia, it is characterised in that: it be using Tarceva as active constituent,
In addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810065353.8A CN110063957A (en) | 2018-01-23 | 2018-01-23 | Tarceva is preparing the purposes in FLT3 inhibitor class drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810065353.8A CN110063957A (en) | 2018-01-23 | 2018-01-23 | Tarceva is preparing the purposes in FLT3 inhibitor class drug |
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| CN110063957A true CN110063957A (en) | 2019-07-30 |
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| CN201810065353.8A Pending CN110063957A (en) | 2018-01-23 | 2018-01-23 | Tarceva is preparing the purposes in FLT3 inhibitor class drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110935027A (en) * | 2019-12-24 | 2020-03-31 | 沈阳药科大学 | Pharmaceutical composition of arsenic trioxide and FLT3 inhibitor and application thereof |
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| US20100286143A1 (en) * | 2009-04-24 | 2010-11-11 | Dora Dias-Santagata | Methods and materials for genetic analysis of tumors |
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2018
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100286143A1 (en) * | 2009-04-24 | 2010-11-11 | Dora Dias-Santagata | Methods and materials for genetic analysis of tumors |
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| HEWING等: "Intravitreal Injection of TIMP3 or the EGFR Inhibitor Erlotinib Offers Protection from Oxygen-Induced Retinopathy in Mice", 《INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110935027A (en) * | 2019-12-24 | 2020-03-31 | 沈阳药科大学 | Pharmaceutical composition of arsenic trioxide and FLT3 inhibitor and application thereof |
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Application publication date: 20190730 |
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