CN106265660B - Purposes of the A674563 in the acute leukemia for carrying FLT3 mutated genes - Google Patents
Purposes of the A674563 in the acute leukemia for carrying FLT3 mutated genes Download PDFInfo
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Abstract
The present invention relates to A674563 in preparation for treating the purposes in the drug for carrying the acute myelocytic leukemia patient of FLT3 mutated genes, wherein the patient with the leukaemia can have or without drug resistance associated with the expression of the height of FL ligand.The invention further relates to the methods that the inhibition of non-treatment purpose carries the Acute Myeloid Leukemia Cells Contributing of FLT3 mutated genes, including the cell is in contact with A674563.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of new application of A-674563 (A674563).
Background technique
Acute myelocytic leukemia (acute myelocytic leukemia, AML) or acute non lymphocytic leukemia
(ANLL) include all non-lymphocyte sources acute leukemia.It is multipotential stem cell or the precursor slightly broken up
Caryogram mutation is formed by a kind of disease, is the Clonal malignant disease of hemopoietic system.Epidemiological survey shows, ring
The onset relation of border, occupation and inherent cause and AML are close.The disease incidence of developed country is higher than developing country, western countries
Higher than oriental countries.Annual morbidity is 2.25/10 ten thousand populations all over the world, and with age increase, disease incidence increases, and 50 years old starts
It is obvious to rise, peak is reached within 60~69 years old, 30 years old or less disease incidence is 1/,100,000, is then up to 17/,100,000 within 75 years old or more.Therefore, AML
Really one kind in, disease of old people, account for the 80%~90% of adult acute leukemia, but only account for acute leukemia 15%~
20%.Meanwhile male's morbidity is higher than women.
FLT3 (Fms-like tyrosine kinase 3) i.e. FMS sample tyrosine kinase 3, with c-Kit, c-FMS and
PDGFR belongs to type III receptor tyrosine kinase (receptor tyrosine kinase III, RTK III) family member,
Extracellular region of its protein structure including 5 immunoglobulin (Ig) spline structure domains composition, 1 transmembrane region, 1 membrane-proximal region (JM),
And it is intracellular be separated by kinase insert 2 tyrosine kinase (TK) areas (S.D.Lyman etc., Oncogene, 1993,
8,815-822).After combining with its ligand FL (FLT3ligand, FL), autophosphorylation occurs FLT3 for tyrosine residue, and
Activation signal is conducted by various cytoplasm proteins, proliferation stimulation is provided, in the self-renewing of candidate stem cell, proliferation, differentiation
Etc. play an important role.FLT3 kinases plays a significant role in the occurrence and development of AML extremely, may pass through following two machine
System is realized: first is that by FLT3 gene mutation, such as there is internal series-connection duplication (internal tandem in FLT3 gene
Duplication, ITD) mutation, the AML patient of numerous studies discovery about one third is prominent with FLT3ITD in the recent decade
Become, nearly spanning domain is caused to extend, kinases space conformation changes, and autophosphorylation occurs simultaneously in the case where ligand is non-dependent
Activation causes the signal transduction of downstream exception, promotes the proliferation and maintenance of leukaemia malignant clone.Just existed first early in 1996
Have found that FLT3 is mutated in AML cell, mutation type is that internal series-connection repeats (FLT3-ITD).In recent years, many to study
The activated mutant of verified FLT3 plays highly important pathological effect in the generation of AML and the progress of disease.Another machine
System is then that AML cell is overexpressed FLT3, and the ligand FL co-expressed with it is by forms such as autocrine, paracrines with wild type FLT3
The schedule of reinforcement of normal signal conduction leads to continuous activation (Kusec R, Jaksic O, OstojicS, the et a1.More of kinases
on prognostic significance of FLT3/ITD size in acute myeloid leukemia(AML)
.Blood, 2006,108:405-406.Kuchenbaner F, Kern W, Sehoeh C, et a1.Detailed analysis
Of ex-pression levels in acute myeloid leukemia.Haematologica, 2005,90:1617-
1625)。
AML patient with FLT3-ITD activated mutant usually have leukocyte counts are high, clinical prognosis is poor,
The unique Clinical symptoms such as easy to recur, and since the detection method of FLT3 activated mutant is simple and easy, therefore more and more grind
The conventional detection means that the person of studying carefully is dedicated to developing into FLT3 AML be used to instruct AML patient treatment and prognosis judgement with
And the detection means as parvovirus B19, and as the another new target spot of leukaemic's chemotherapeutics.
There are mainly two types of the activated mutants for having confirmed FLT3: one is go here and there inside 14,15 exons of nearly spanning domain
Connection repeats (internal tandem duplication, ITD)；Another kind is tyrosine kinase domain (tyrosine
Kinase domain, TKD) 20 exons point mutation (point mutation, PM), multidigit in its activate ring in, most often
See be the 835th asparatate (ASP 835) residue mutation, such as D835Y.Two kinds of mutation can cause FLT3 tyrosine
The constitutive activation of kinases.In the physiological state, the expression of FLT3 is only limited to the candidate stem cell of CD34+, ligand FL,
In the presence of ligand, nearly spanning domain forms FLT3 dimer and has activated inhibiting effect, as ligand FL and FLT3 receptor knot
It closes, the latter's generation is Dimerized, so that the conformation of kinase domain changes, tyrosine residue phosphorylation, RAS-GAP,
The substrate proteins such as PLC- γ, PI3K, STAT5 and ERK1/2 are activated, and are transmitted by a series of Intracellular signals, cell Proliferation letter
It number transduces into nucleus, causes candidate stem cell that proliferation and activation occurs.It has been demonstrated that the internal series-connection of FLT3 membrane-proximal region
Duplication and activation circling point mutation resulted in FLT3 kinases constitutively activated and downstream target activation, including STAT5 and
RAS/MAPK access.Both activated mutants of FLT3 are responsible for FLT3 and autophosphorylation occur and then FLT3 is caused to match
The constitutively activated of body dependent/non-dependent further activates signal transduction abnormal downstream, to play promotion proliferation and inhibit
The effect of apoptosis, so that leukaemic's clinical prognosis with this mutant phenotype is poor.
Research hotspot is become to the targeted inhibition of FLT3 gene mutation at present, predominantly the suppression of exploitation small molecule tyrosine kinase
Preparation inhibits its activity and competing ATP-binding site with FLT3 tyrosine kinase.Clinical inhibition is come at present
The kinase inhibitor of FLT3 has AC220, TCS359 etc..However it has been found that being existed using some AML patients that these drugs are treated
Drug resistance can be generated to therapeutic agent by treating the later period, this is because the height with the ligand FL (FLT3 Ligand) of FLT3 coexpression
Caused by expression.
A674563 is a kind of inhibitor of protein kinase AKT (also referred to as protein kinase B: PKB), can be to be used alone
Or the mode used with other therapeutic agents is for treating autoimmune disease or illness, heteroimmunity disease or disease
Disease, cancer include lymthoma and inflammatory disease or illness.Currently, yet there are no prominent about using A674563 treatment to carry FLT3
The related report of the acute myelocytic leukemia of modification gene also has no about using the A674563 treatment to have and FL ligand
Height expresses the relevant report of the acute myelocytic leukemia patient of the carrying FLT3 mutated genes of associated drug resistance.
Summary of the invention
In view of aforementioned technical problem, inventor is conducted extensive research.As a result, inventor it was unexpectedly observed that
This AKT kinase inhibitor of A674563 can effectively treat the acute myelocytic leukemia for carrying FLT3 mutated genes, and
It can be used for treating the acute myeloid with the carrying FLT3 mutated genes for expressing associated drug resistance with the height of FL ligand
Leukaemic.Specifically, inventors have found that A674563 is to carrying FLT3-ITD and/or FLT3-D835Y mutated genes
Acute Myeloid Leukemia Cells Contributing such as MOLM-13, MOLM-14, MV-4-11 etc. play stronger inhibiting effect (GI50 difference
It is 0.1 μM, 0.22 μM, 0.12 μM)；Meanwhile be added FLT3 ligand FL with stimulate cell drug resistance test in, A674563
To Acute Myeloid Leukemia Cells Contributing such as MOLM-13, the MOLM- for carrying FLT3-ITD saltant type and wild type FLT3 gene simultaneously
14 cells also all play stronger inhibiting effect.Therefore, A674563 is applicable to clinical treatment and carries FLT3 mutated genes spy
It is not the acute myelocytic leukemia patient of FLT3-ITD and/or FLT3-D835Y mutated genes.Further, which can
With drug resistance associated with the expression of the height of FL ligand.
On the one hand, the present invention relates to A674563 (especially carries in preparation for treating carrying FLT3 mutated genes
FLT3-ITD and/or FLT3-D835Y mutated genes) acute myelocytic leukemia patient drug in purposes.Further
Ground, the patient can have drug resistance associated with the expression of the height of FL ligand.
Over the course for the treatment of, which according to circumstances can combine individually or with one or more other therapeutic agents and make
With.Can by injecting, taking orally, suck, at least one of rectum and transdermal administration by the medicament administration comprising A674563 to
Carry the acute myelocytic leukemia patient of FLT3 mutated genes.Other therapeutic agents can be selected from following drug: immune suppression
Preparation (such as tacrolimus, cyclosporin, rapamycin, methotrexate (MTX), cyclophosphamide, imuran, mercaptopurine, wheat examine phenol
Ester or FTY720), glucocorticoids medicine (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone,
Betamethasone, triamcinolone, fluorine hydroxyl prednisolone, beclomethasone, fludrocortisone acetate, percorten, aldehyde are solid
Ketone), non-steroidal anti-inflammatory drugs (such as salicylate, aryl alkanoic acid, 2- arylpropionic acid, N- aryl-anthranilic acid, former times health class,
Examine former times class or sulphonanilid), allergic reaction bacterin, antihistamine, anti-leukotriene medicine, beta-2-agonists, theophylline, anticholinergic agent or
Other selective kinase inhibitors (such as mTOR inhibitors, c-Met inhibitor) or her2 antibody-drug.In addition, other treatments
Agent can also be rapamycin (Rapamycin), gram azoles for Buddhist nun (Crizotinib), tamoxifen, Raloxifene, Ah Nagqu
Azoles, Exemestane, Letrozole, TrastuzumabTM(Herceptin), GleevecTM(Imatinib), taxolTM(taxol), ring
Phosphamide, Lovastatin, U.S. promise tetracycline (Minosine), cytarabine, 5 FU 5 fluorouracil (5-FU), methotrexate (MTX) (MTX),
TaxotereTM(docetaxel), ZoladexTM(Goserelin), vincristine, vincaleukoblastinum, nocodazole, Teniposide, support
Moor glycosides, gemzarTM(gemcitabine), Epothilones (Epothilone), promise only sheet, camptothecine, daunorubicin
(Daunonibicin), dactinomycin D, mitoxantrone, amsacrine, Doxorubicin (adriamycin), epirubicin or Yi Da
Compare star.Alternatively, other therapeutic agents are also possible to cell factor such as G-CSF (granulocyte colony stimulating factor).Alternatively, other control
Treating agent also can be used in combination in same therapeutic scheme, such as, but not limited to, CMF scheme (cyclophosphamide, methotrexate (MTX) and 5- fluorine urine
Pyrimidine), CAF scheme (cyclophosphamide, adriamycin and 5 FU 5 fluorouracil), AC scheme (adriamycin and ring phosphinylidyne
Amine), FEC scheme (5 FU 5 fluorouracil, epirubicin and cyclophosphamide), ACT or ATC scheme (adriamycin, cyclophosphamide
And taxol) or CMFP scheme (cyclophosphamide, methotrexate (MTX), 5 FU 5 fluorouracil and prednisone).
On the other hand, the invention further relates to a kind of pharmaceutical compositions, and it includes A674563 and pharmaceutically acceptable load
Body or auxiliary agent.The composition can also further include one or more other therapeutic agents.Other therapeutic agents described herein
As defined above.
It yet still another aspect, the present invention relates to the acute myeloid for using A674563 treatment to carry FLT3 mutated genes is white
The method of blood patient, wherein the patient can have or without drug resistance associated with the expression of the height of FL ligand.?
In therapeutic process, can by injecting, taking orally, suck, rectum or percutaneously by A674563 be administered to carry FLT3 mutated genes
The acute myelocytic leukemia patient of (especially carrying FLT3-ITD and/or FLT3-D835Y mutated genes), the wherein trouble
Person can have or without drug resistance associated with the expression of the height of FL ligand.It can also according to circumstances will be a effective amount of
A674563 individually or with one or more other therapeutic agents is applied in combination.Mentioned other therapeutic agents as limited above
It is fixed.Over the course for the treatment of, the chemotherapy for using A674563 can also be combined radiotherapy to be administered.
It yet still another aspect, the present invention relates to a kind of Acute Myeloid Leukemia Cells Contributings for inhibiting to carry FLT3 mutated genes
Method, including the cell is in contact with A674563.The method can be used for therapeutic purposes either non-treatment mesh
's.Further, the cell can not live through or live through in advance the processing of FLT3 inhibitor.According to the present invention, described
Cell is preferably selected from one of MOLM-13, MOLM-14, MV-4-11 or a variety of.It is further preferred that by the cell with
The A674563 that effective concentration is at least 0.01 μM is in contact, and the amount of more preferable A674563 is at least 0.1 μM, further preferably
0.2-10 μM, such as 0.2-3 μM.
In another aspect, the present invention relates to A674563 in preparation for inhibiting the acute marrow of carrying FLT3 mutated genes
Purposes in the drug of cell leukemia cell.Specifically, which carries FLT3-ITD mutated genes or LT3-D835Y is prominent
Modification gene, and the cell can be selected from one of MOLM-13, MOLM-14 and MV-4-11 or a variety of.
Detailed description of the invention
It is opposite to FLT3 in MOLM-14, MOLM-13 and MV-4-11 cell respectively that Fig. 1 a-1c shows various inhibitor
The influence of closely related albumen and associated signal paths, wherein 1a: the A674563 and control inhibitor of various concentration are to FLT3
The influence of relatively closely related albumen and associated signal paths；1b: when adding FL ligand or not adding FL ligand, A674563
The comparison result of influence to FLT3 relatively closely related albumen and associated signal paths；1c: addition FL ligand does not add
When FL ligand, the comparison result of influence of the MLN518 to FLT3 relatively closely related albumen and associated signal paths is compareed.
Fig. 2 shows the influences of FLT3 autophosphorylation in the BaF3 cell line of A674563 equity gene loci.
Fig. 3 shows A674563 respectively to the influence of the Apoptosis of MOLM-13, MOLM-14, MV-4-11.
Fig. 4 a-4c shows A674563 respectively to the cell cycle point of MOLM-13 (a), MOLM-14 (b), MV-4-11 (c)
The influence of cloth.
Specific embodiment
Before the present invention is further described, for a better understanding of the present invention, some terms are illustrated.
Definition
" A674563 " is a kind of inhibitor of protein kinase B (PKB/AKT).Inhibit as a kind of small molecule PKB/AKT
Agent, A674563 have structure shown in following formula (I):
FLT3 (Fms-like tyrosine kinase 3) i.e. FMS sample tyrosine kinase 3.
FLT3-ITD mutated gene or FLT3-ITD mutated genes refer to that transmembrane region internal series-connection repeats (FLT3
Internal tandem duplication, FLT3-ITD) mutation is acute myeloid leukemia (acute myeloid
Leukaemia, AML) in incidence highest and mutation relevant to prognosis.
FLT3-D835Y mutated gene or FLT3-D835Y mutated genes refer to the 20 of tyrosine kinase domain (TKD)
Point mutation occurs for exon: the 835th asparatate (Asp835) residue mutations are tyrosine (Tyr), are abbreviated as D835Y.
Terms used herein " administration " or " application " include being introduced into compound in subject to realize its predetermined function
With the approach of effect.The example for the administration route that can be used includes injection (subcutaneous injection, intravenous injection, parenteral injection, abdomen
Injection, intrathecal injection in film), oral, sucking, rectum and percutaneous etc..It can be applied by way of being suitable for various administration routes
Use pharmaceutical preparation.
Terms used herein " pharmaceutically acceptable " refer to, in the range of reasonable medical judgment, suitable for
The tissue of people and other mammals contacts without excessive toxicity, stimulation, allergic reaction etc., and with reasonable interests/wind
The component that danger ratio matches.
Terms used herein " effective quantity " include effectively reaching desired with regard to dosage and for the necessary time cycle
As a result (such as, it is sufficient to treat disease or illness described herein) amount.The effective quantity of the compounds of this invention can be according to example
As different such as following factor: morbid state, age and the weight and compound of subject is in cell or in subject
Cause the ability etc. of desired response.Adjustable dosage regimen is to provide optimal therapeutic response.
" drug resistance " (drug resistance) means microorganism, helminth and tumour cell etc. for chemotherapeutics
The tolerance of effect, once generating, the Chemotherapy of drug is just decreased obviously drug resistance.Drug resistance can divide according to its occurrence cause
To obtain drug resistance and natural bacterial drug resistance.For anti-tumor drug, tumour cell generates anti-malignant tumor medicine insensitive existing
As being drug resistance, it is the major reason of chemotherapy of tumors failure, is also chemotherapy of tumors urgent need to solve the problem.It is according to the present invention
Drug resistance totally refers to that the AML patient for carrying FLT3 mutated genes is undergoing AML drug (such as FLT3 suppression other than A674563
Preparation) treat generated drug resistance later.
In embodiments of the present invention, according to the present invention to the tested of the AML for carrying FLT3 mutated genes
Person (subject including generating drug resistance in the previous tretament for the AML for carrying FLT3 mutated genes) application
When A674563 is treated, the amount for giving drug depends on factors, such as specific dosage regimen, disease or implant treatment
And its (such as weight, gender, age, the patient are before this uniqueness of seriousness, subject in need for the treatment of or host
It is no to live through other treatment (treatment carried out for example, by using FLT3 inhibitor) etc.), still, according to specific situation, including example
Such as the subject or host of the specific drug, administration route, the illness for the treatment of and the treatment that have used, administration dosage can be by
Methods known in the art routinely determine.In general, administration dosage is typically in 0.02- for the dosage that adult treatment uses
5000mg/ days, for example, about 1-1500mg/ days ranges.The required dosage is expressed as one or is administered simultaneously in which can be convenient
(or in a short time) or divided dose at interval appropriate, such as daily two, three, four doses or more divided agent.This field skill
Art personnel it is understood that although giving above-mentioned dosage range, the effective quantity of A674563 can according to the case where patient simultaneously
It is suitably adjusted in conjunction with doctor diagnosed.
As previously mentioned, the subject for carrying the AML of FLT3 mutated genes mentioned by the present invention can be prior experience
The subject for crossing AML treatment is also possible to not live through the subject of associated treatment in advance.In some embodiments, tested
Person lives through the treatment carried out using FLT3 inhibitor in advance, and generates drug resistance to previous tretament (or the I phase treats).Another
In a little embodiments, subject lives through the treatment carried out using FLT3 inhibitor in advance, and (or the I phase is controlled to previous tretament
Treat) drug resistance is not generated.In the above-described embodiment, these patients can be carried out with A674563 used according to the invention
Treatment.
" GI50 " used herein is that the growth of 50% cell is instigated to be suppressed required drug concentration, i.e., drug makes 50% thin
The drug concentration when growth of born of the same parents' (such as cancer cell) is suppressed or controls.
" IC50 " used herein is also known as half-inhibitory concentration, refers to and obtains maximum in the analysis for measuring certain effect
The 50% of effect inhibits amount, concentration or the dosage of special inhibitor when (such as inhibition to PKB/AKT kinase activity).
" EC50 " used herein refers to dosage, concentration or the amount for measuring such compound, the dosage, concentration or amount
Cause the dose-dependant reaction of 50% maximum expression of the induction of particular assay compound, stimulation or the specific reaction reinforced.
Application of the invention
In certain embodiments of the present invention, A674563 is applied according to the present invention carry FLT3 saltant type base to treat
The acute myelocytic leukemia of cause, wherein the patient with the leukaemia can have or express without the height with FL ligand
Associated drug resistance.Treatment may include single therapy, also may include serial therapy.
In certain embodiments of the present invention, can it is to patient daily, the next day or apply doses weekly
A674563, and continue 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11
A month, 1 year or several years.It is understood that can be during treatment according to patient's feelings to the dosage of the A674563 of patient's application
Condition and Treatment need and suitably increase or decrease.
In certain embodiments of the present invention, can simultaneously or sequentially to subject apply A674563 and it is a kind of or
A variety of others therapeutic agents.Alternatively, in certain embodiments of the present invention, a kind of pharmaceutical composition can be applied to subject
Object, the composition are formulated as comprising A674563 and pharmaceutically acceptable carrier or auxiliary agent, and it is optional it is one or more its
Its therapeutic agent.
A674563 for above-mentioned treatment can be formulated into suitable pharmaceutical preparation, for use in oral administration (example
Such as, to be dissolved in the such as aqueous liquid form of solvent or water-free liquid or in solid carrier), per rectum administration, stomach
External administration, administration in brain pond, Intraperitoneal medication, local administration (pass through pulvis, ointment, lotion, gelling agent, drops, transdermal patch
Agent or transdermal skin patches), oral administration, through bronchus form or as mouth sprays or nasal spray etc..Specifically, A674563
It can be formulated into, for example, solution, suspension, tablet, dispersible tablet, pill, capsule, pulvis, sustained release for oral administration
Preparation or elixir etc..In the embodiment of drug administration by injection, A674563 can also be configured to suitable injection.
Can daily, weekly, monthly, every other month, quarterly or by any other administration schedule with single dose injection or infusion,
Multi-dose is administered with continuous dosage form.The administration of invention formulation can be intermittent to subject, or in gradually
Into, continuous, constant or controlled speed.In addition, the number of the time of form of administration and daily administration dosage form can not in one day
Together.In certain embodiments of the present invention, be administered to patient A674563 preparation can at 0.02-5000mg/ days, such as
About 1-1500mg/ days ranges.The required dosage be expressed as with can be convenient it is one or be administered simultaneously (or in the short time
It is interior) or divided dose at interval appropriate, such as daily two, three, four doses or more divided agent.
The pharmaceutical composition comprising A674563 for above-mentioned treatment can be formulated into solution, suspension, tablet, divide
The dosage forms such as discrete piece, pill, capsule, pulvis, sustained release preparation or elixir.The composition can contain 0.02-5000mg's
A674563, but the effective dose of used active constituent can be according to specifically used dosage regimen, administration route, He Beizhi
The severity of the illness for the treatment of is different and changes.Technical staff is appreciated that the effective dose for each patient can be according to disease
Severity, individual inheritance variation or metabolic rate are different and change.However, usually with the daily dosage of about 0.5-1000mg,
Optional one day 2-4 times divided dose or when giving the compounds of this invention with sustained release forms, obtains desired result.Plan total agent daily
Measure about 1-1000mg, preferably about 2-500mg.
It will illustrate the present invention by embodiment and in conjunction with attached drawing below.It should be understood that the embodiment and attached drawing shown are only used
The present invention is understood in help, but is not construed as limiting the invention.
Embodiment
Experimental material: carrying out experiment of the invention using the AKT inhibitor A674563 of various concentration in embodiment, and
Use PKB/AKT inhibitor C CT128930, PKB/AKT inhibitor GDC0068, PKB/AKT inhibitor GSK690693, PKB/
As control, (these drugs are purchased from Hao to AKT inhibitor MK2206, FLT3 inhibitor MLN518, FLT3 inhibitor TCS359
Yuan Chemexpress company (Shanghai)).
Influence of the embodiment 1:A674563 to cancer cell multiplication
Influence by test A674563 to growth of cancer cells, assessment A674563 inhibit the selectivity of cancer cell multiplication.
Acute myeloid leukemia cells in children HL-60 (expression wild type FLT3 gene), acute early children have been selected in the present embodiment
Granulocytic leukemia cell strain NB-4 (Lu+) (expression wild type FLT3 gene), human muscle creatine kinase cell strain OCI-
AML-3 (expression FLT3 A680V mutated genes), (expression FLT3-ITD is prominent by human muscle creatine kinase cell strain MOLM-14
Modification gene and wild type FLT3 gene), human muscle creatine kinase cell strain MOLM-13 (expression FLT3-ITD saltant type base
Because and wild type FLT3 gene), human muscle creatine kinase cell strain MV-4-11 (expression FLT3-ITD mutated genes),
MDS-RAEB (myelodysplastic syndrome-initial cell increases type) cell strain SKM-1 (expression wild type FLT3 gene), people
Acute myeloid leukemia cells in children strain U-937 (expression wild type FLT3 gene), mouse cell BaF3.The above cell is purchased from
ATCC.Mouse TEL-FLT3-BaF3 (stablizing expression FLT3WT kinases) cell, mouse BaF3-FLT3-ITD (stablize expression FLT3
The activated protein kinase of ITD mutation) cell, mouse BaF3-FLT3-D835Y (activated protein kinase for stablizing expression FLT3-D835Y mutation)
Cell, mouse BaF3-FLT3-ITD-D835Y (stablize expression FLT3-ITD and FLT3-D835Y mutation activated protein kinase) cell,
Mouse BaF3-FLT3-ITD-F691L (activated protein kinase for stablizing expression FLT3-ITD and FLT3-F691L mutation) cell is by this
Laboratory building, construction method are as follows: expand the mankind FLT3, FLT3-ITD, FLT3-D835Y, FLT3-ITD+ respectively through PCR
FLT3-D835Y, FLT3-ITD+FLT3-F691L kinases region sequence, and the segment of amplification is inserted respectively into N-terminal TEL or
The pMSCV-Puro carrier (being purchased from Clontech, the U.S.) of person's TPR segment, passes through reverse transcription Murine Embryonic Stem
Cell Virus (MESV) mouse embryo stem cell virus (viral package carrier pMSCV-puro is purchased from Clontech, the U.S.) side
Method is stablized and is transferred to mouse BaF3 cell, and the mouse BaF3 cell culture medium of the above building is RPMI 1640 plus 10%FBS (small
Ox embryo serum) and 1%P/S (dual anti-), and IL-3 growth factor is removed, finally obtain expression FLT3-ITD, FLT3-
D835Y, FLT3, FLT3-ITD+FLT3-D835Y, FLT3-ITD+FLT3-F691L are transferred to the cell line of albumen.
In embodiment by various concentration (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μ
M, 0.123 μM, 0.370 μM, 1.11 μM, 3.33 μM, 10 μM in DMSO) A674563 individually or simultaneously with 1ng/mL,
The FLT3 ligand FL (being purchased from CST Cell Signing Technology, the U.S.) of 5ng/mL or 10ng/mL, is added to above-mentioned
In cell, then by cell in incubator 37 degree be incubated for 72 hours, with Cell Titer-(Promega, the U.S.) chemistry
Self-luminous method cell viability detection kit detects number of viable cells by being quantitative determined to the ATP in living cells.?
To result shown in following table 1 (not adding FLT3 ligand FL) and table 2 (addition FLT3 ligand FL) respectively.
As shown in table 1, discovery A674563 is to human muscle creatine kinase cell strain MOLM-14 (expression FLT3-ITD mutation
Type gene and wild type FLT3 gene), human muscle creatine kinase cell strain MOLM-13 (expression FLT3-ITD mutated genes
And wild type FLT3 gene), this three plants of human muscle creatine kinase cell strain MV-4-11 (expression FLT3-ITD mutated genes)
The proliferation of cancer cell significantly inhibits, and wherein A674563 is to cell strain MOLM-13, MOLM-14 and MV-4-11
GI50 is respectively 0.1 μM, 0.22 μM, 0.12 μM, and to the proliferation of other cancer cells for only carrying wild type FLT3 gene without bright
Aobvious inhibiting effect.Meanwhile A674563 is transferred to cell (the mouse BaF3- of albumen to the dependence FLT3-ITD that this laboratory constructs
FLT3-ITD cell) and rely on FLT3-D835Y be transferred to albumen cell (mouse BaF3-FLT3-D835Y cell) proliferation
There is strong inhibiting effect, GI50 is respectively 0.088 μM, 0.075 μM.In contrast, A674563 is transferred to FLT3 WT is relied on
The basic unrestraint effect of the proliferation of the cell (TEL-FLT3-BaF3 cell, GI50=1.0 μM) of albumen.
Measurement result of the table 1.A674563 to the inhibitory effect of cancer cell
Measurement result of the continued 1.A674563 to the inhibitory effect of cancer cell
In the test of addition FLT3 ligand FL (as shown in table 2 below), we are it is obvious that carrying FLT3-ITD
1ng/ml is added in human muscle creatine kinase cell strain MOLM-13, MOLM-14 of mutated genes and wild type FLT3 gene
FLT3 ligand FL after, FLT3 inhibitor TCS359 obviously loses activity；Another FLT3 inhibitor MLN518 is being carried
In human muscle creatine kinase cell strain MOLM-13, MOLM-14 of FLT3-ITD mutated genes and wild type FLT3 gene with
The increase of FLT3 ligand FL amount that is added its active also decrease；In contrast, FLT3-ITD mutated genes are being carried
And in human muscle creatine kinase cell strain MOLM-13, MOLM-14 of wild type FLT3 gene, with the FLT3 ligand of addition
The increase of FL amount, A674563 activity is almost without any variation of generation.It is acute myelogenous in the people for only carrying FLT3 mutated genes
In leukemia cell line MV-4-11, if addition FL does not also influence the cell inhibitory activity of A674563 substantially.
Table 2 the result shows that, the active function of A674563 is not influenced substantially by existing for FL ligand.Therefore, even
In the case that the acute myeloid leukemia cells in children of carrying FLT3 mutated genes generates drug resistance due to ligand FL secretion increase,
A674563 can also play apparent inhibiting effect to it.It means that A674563, which can be applied to treatment, to be had and FL ligand
Height express associated drug resistance carrying FLT3 mutated genes acute myelocytic leukemia.
The measurement result of A674563 to the inhibitory effect of cancer cell in the case where adding the FL of various concentration of table 2.
To sum up, embodiment 1 the result shows that A674563 for carry FLT3 mutated genes acute myeloid leukaemia it is thin
The proliferation of born of the same parents has very strong inhibiting effect, especially to the acute myelogenous of carrying FLT3-ITD, FLT3-D835Y mutated genes
The proliferation of leukaemia cell has inhibiting effect strongly.The result of embodiment 1 also illustrates that A674563 can be used for treating FL
The expression of ligand height causes the acute myeloid leukaemia of the carrying FLT3 mutated genes of drug resistance.
Influence of the embodiment 2:A674563 to upstream and downstream signal path in cell
In human muscle creatine kinase cell MV-4-11 (expression FLT3-ITD mutated genes) cell strain, the acute marrow of people
Property leukemia cell line MOLM-13 (expression FLT3-ITD mutated genes and wild type FLT3 gene) and the acute myelogenous white blood of people
It is many by measurement in disease cell line MOLM-14 (expression FLT3-ITD mutated genes and wild type FLT3 gene) cell strain
Cellular biochemistry terminal and functional terminal, have evaluated A674563 to FLT3 protein kinase, PKB/AKT kinases in cell with
And with FLT3 kinases, PKB/AKT kinases closely related Protein S TAT5, ErK, GSK3 β, FOX01, PRAS40, p70S6K,
The influence of the phosphorylation of 4EBP1.We also have detected A674563 to PROTEIN C-Myc and transcription factor NF-KB subunit simultaneously
The influence (Fig. 1 a) of p65 phosphorylation.With 0 μM of various concentration, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM (in DMSO)
A674563 and 1 μM (in DMSO) PKB/AKT inhibitor GSK690693, PKB/AKT inhibitor MK2206, FLT3 inhibits
Agent TCS359 handles the acute of three plants of MOLM-13, MOLM-14, MV-4-11 (Fig. 1 a) carrying FLT3-ITD mutated genes respectively
Marrow leukaemia cell 4 hours, while (Corning is purchased from the culture medium for containing only 1%FBS (calf serum)
Incorporated, the U.S.) by cell Nature enemy 4 hours, collect cell sample.Compound is measured in this three plants of cells
The influence of STAT5, ErK, GSK3 β, FOX01, PRAS40, p70S6K, 4EBP1, C-Myc, NF- κ B p65, AKT protein phosphorylation
(referring to Fig. 1 a).
As shown in Figure 1a, in tri- plants of cells of human muscle creatine kinase cell MOLM-13, MOLM-14, MV-4-11,
A674563 has a strong inhibiting effect to the phosphorylation of the downstream FLT3-ITD albumen STAT5 in cell, and to FLT3 albumen
Closely related PROTEIN C-the Myc of kinases has apparent degradation.In same experiment, control compound PKB/AKT inhibitor
GSK690693, PKB/AKT inhibitor MK2206 do not influence the phosphorylation of FLT3 kinases, to the downstream FLT3-ITD albumen
The phosphorylation of STAT5 also has not significant impact, and does not also drop significantly to the PROTEIN C-Myc closely related with FLT3 protein kinase
Solution effect.Another control compound FLT3 inhibitor TCS359 can consumingly inhibit the albumen closely related with FLT3-ITD
The phosphorylation of STAT5 also has apparent degradation to the PROTEIN C-Myc closely related with FLT3 protein kinase.This shows
A674563 is able to suppress the phosphorylation of the signal path downstream albumen STAT5 of protein kinase FLT3 in cell, and then inhibits to carry
The cell of the acute myeloid leukemia cells in children strain of FLT3-ITD gene or carrying FLT3-ITD gene and FLT3 WT gene increases
It grows.
(as shown in Fig. 1 b, 1c, use MLN518 as control) in the test of addition FLT3 ligand FL, will use
The FL of 10ng/ml stimulates 2 hours results and does not apply the Comparative result of stimulation, and A674563 and MLN518 are to signal in cell
The influence of access is different.In the human muscle creatine kinase for carrying FLT3-ITD mutated genes and wild type FLT3 gene
It in cell strain MOLM-14, is added before and after the FLT3 ligand FL of 10ng/ml, A674563 (such as Fig. 1 b) can be significantly
Inhibit the phosphorylation of STAT5, and also have apparent degradation to the PROTEIN C-Myc closely related with FLT3 protein kinase, says
Influence of the bright A674563 to signal path in cell is not influenced by existing for FL ligand.Therefore, even carrying FLT3 mutation
The acute myeloid leukemia cells in children of type gene generates drug resistance since the ligand FL secretion co-expressed with FLT3 increases after medication
In the case where property, A674563 also has apparent effect to its signal path.In same experiment, control compound FLT3 inhibits
Agent MLN518 (as illustrated in figure 1 c) can consumingly inhibit close with FLT3-ITD in the FLT3 ligand FL that 10ng/ml is not added
The phosphorylation of relevant Protein S TAT5 also has apparent degradation to make the PROTEIN C-Myc closely related with FLT3 protein kinase
With.But after the FLT3 ligand FL of 10ng/ml is added, MLN518 couples of PROTEIN C-Myc's closely related with FLT3 protein kinase
Degradation obviously weakens, and illustrates that control compound FLT3 inhibitor MLN518 is resistance to for generating because of ligand FL secretion increase
The signal path impact effect of medicine cell strain weakens.In contrast, acute myelogenous white in the people for only carrying FLT3 mutated genes
In blood disease cell line MV-4-11, because wild type FLT3 gene is not present, so even addition FL, is also not present and FL ligand
Height express associated drug resistance.Experimental result is shown, in MV-4-11 cell strain, before and after adding FL,
A674563 (Fig. 1 b) influences the signal path of cell strain essentially the same.Control compound FLT3 inhibitor MLN518 (Fig. 1 c)
The signal path of cell strain is influenced also almost the same.
The test result of addition FLT3 ligand FL further proves that A674563 in cell to believing from the level of signal path
The influence of number access is not influenced by existing for FL ligand, therefore A674563 can be applied to treatment has high table with FL ligand
Up to the acute myelocytic leukemia of the carrying FLT3 mutated genes of associated drug resistance.
The influence of FLT3 autophosphorylation in the BaF3 cell line of embodiment 3:A674563 equity gene loci
Using mouse TEL-FLT3-BaF3 (activated protein kinase for stablizing expression wild type FLT3) cell, mouse BaF3-
FLT3-ITD (activated protein kinase for stablizing expression FLT3 ITD mutation) cell, mouse BaF3-FLT3-D835Y (stablize expression FLT3
D835Y mutation activated protein kinase) cell, mouse BaF3-FLT3-ITD-D835Y (stablize expression FLT3-ITD+D835Y mutation
Activated protein kinase) cell, mouse BaF3-FLT3-ITD-F691L (activated protein kinase for stablizing expression FLT3-ITD+F691L mutation) be thin
Born of the same parents (construction method of these cells is referring to embodiment 1).A674563 is tested in above-mentioned cell line to the FLT3 in cell
And/or the influence (Fig. 2) of the autophosphorylation of the protein kinase of FLT3-ITD saltant type.With 0 μM of various concentration, 0.03 μM, 0.1
μM, 0.3 μM, 1 μM, 3 μM (in DMSO) of A674563,0.05 μM (in DMSO) of FLT3 kinase inhibitor AC220 (purchase
From Hao Yuan Chemexpress company (Shanghai)) the different BaF3 cell line (TEL-FLT3- for waiting gene locis are handled respectively
BaF3, BaF3-FLT3-ITD, BaF3-FLT3-D835Y, BaF3-FLT3-ITD-D835Y, BaF3-FLT3-ITD-F691L), 4
Cell is collected after hour, the influence (Fig. 2) through Western Blot detection A674563 to FLT3 kinases autophosphorylation.
The determination data of the influence of FLT3 autophosphorylation such as table 3 in the BaF3 cell line of A674563 equity gene loci
Shown: in the BaF3 cell line of all equal gene locis in the present embodiment, A674563 is to the protein kinase in cell line
The autophosphorylation of FLT3 has a certain impact, and especially mouse BaF3-FLT3-ITD (stablizes the work of expression FLT3 ITD mutation
Change kinases) and mouse BaF3-FLT3-D835Y (activated protein kinase for stablizing expression FLT3 D835Y mutation) cell strain, EC50 points
It is not 0.085 μM, 0.045 μM (referring to table 3).In same experiment, FLT3 kinase inhibitor AC220 is compareed to protein kinase
The autophosphorylation of FLT3 also has obviously inhibiting effect (referring to fig. 2).Embodiment 3 shows that A674563 can be different etc.
Inhibit the autophosphorylation of protein kinase FLT3 in the BaF3 cell line of gene loci.
The determination data of the influence of FLT3 autophosphorylation in the BaF3 cell line of table 3.A674563 equity gene loci
| Cell strain title | A674563 p-FLT3:EC50(μM) |
| TEL-FLT3-BaF3 | 0.87 |
| BaF3-FLT3-ITD | 0.085 |
| BaF3-FLT3-D835Y | 0.045 |
| BaF3-FLT3-ITD-F691L | 0.4 |
P-FLT3: the FLT3 of phosphorylation.
Embodiment 4:A674563 is in cell to the influence of Apoptosis
In order to prove that the death of cell after medication is caused by apoptosis or necrosis, FLT3-ITD saltant type is being carried
Acute myeloid leukemia cells in children MOLM-13, MOLM-14, MV-4- of gene or FLT3-ITD mutated genes+FLT3 WT gene
In 11 cells, A674563 is had detected in cell to the DNA repair enzyme poly- adenosine diphosphate-core closely related with Apoptosis
The influence of sugared polymerase PARP, 3 protein cleavage of aspartic acid proteolytic enzyme Caspase containing cysteine.Use various concentration
0 μM, 0.3 μM, 1 μM, 3 μM (in DMSO) of A674563,1 μM (in DMSO) of FLT3 kinase inhibitor TCS359,1 μM
The PKB/AKT kinase inhibitor MK2206 of (in DMSO), 1 μM (in DMSO) of PKB/AKT kinase inhibitor GSK690693
MOLM-13, MOLM-14, MV-4-11 cell are handled respectively, collect cell after 24 hours.It is different dense with Western Blot detection
The medicine of degree adenosine diphosphate-ribose polymerase PARP poly- to DNA repair enzyme and the aspartic acid proteolytic enzyme containing cysteine
The influence of the shear protein of Caspase 3.
Experimental result is as shown in Figure 3: for MOLM-13 and MV-4-11 cell, when A674563 Drug level is 0.3 μM
When, just it can be seen that obviously the poly- adenosine diphosphate of DNA repair enzyme-ribose polymerase PARP is cut after effect 24 hours
It cuts and the shearing of the particularly apparent aspartic acid proteolytic enzyme Caspase 3 containing cysteine.It is right in same experiment
According to the use of FLT3 kinase inhibitor TCS359, PKB/AKT kinase inhibitor MK2206, PKB/AKT kinase inhibitor GSK690693
When concentration is 1 μM, after effect 24 hours, above-mentioned phenomenon is not apparent.For MOLM-14 cell, when A674563 medication
When concentration is 1 μM, it can be seen that the obviously poly- adenosine diphosphate-ribose polymerase of DNA repair enzyme after effect 24 hours
The shearing of PARP and the shearing of the particularly apparent aspartic acid proteolytic enzyme Caspase 3 containing cysteine.Same reality
In testing, FLT3 kinase inhibitor TCS359, PKB/AKT kinase inhibitor MK2206, PKB/AKT kinase inhibitor are compareed
When the Drug level of GSK690693 is 1 μM, after effect 24 hours, poly- two phosphorus of adenosine of apparent DNA repair enzyme is not observed
Acid-ribose polymerase PARP shearing and the shearing of the aspartic acid proteolytic enzyme Caspase 3 containing cysteine.Cause
This, embodiment 4 the result shows that A674563 causes the acute myeloid leukemia cells in children for carrying FLT3-ITD mutated genes to wither
Die (rather than meronecrosis).
The influence of embodiment 5:A674563 cell cycle in cell
In order to study which growth cycle cell after medication is stopped in, carry FLT3-ITD mutated genes or
Acute myeloid leukemia cells in children MOLM-13, MOLM-14, MV-4-11 cell of FLT3-ITD mutated genes+FLT3 WT gene
In strain, influence of the A674563 to the cell cycle distribution of these cell strains is tested.With 0 μM of various concentration, 0.3 μM, 3 μM
The A674563 of (in DMSO), 1 μM (in DMSO) of FLT3 kinase inhibitor TCS359,1 μM (in DMSO) of PKB/
AKT kinase inhibitor MK2206,1 μM (in DMSO) of PKB/AKT kinase inhibitor GSK690693 act on acute myelogenous white
Blood disease cell MOLM-13, MOLM-14, MV-4-11 collect cell, are washed twice with 1 × PBS buffer solution after effect 24 hours,
75% ethyl alcohol of the cell of washing is fixed 24 hours in -20 DEG C, is washed twice again with 1 × PBS buffer solution, add 0.5mL 1 ×
The PI dyeing liquor (being purchased from U.S. BD Bioscience) of PBS buffer solution and 0.5mL are into cell and cell is placed in dark keeps away
37 DEG C of light are dyed 15 minutes, detect cell cycle distribution with flow cytometer (BD FACS Calibur).
Experimental result is as shown in Figure 4: in acute myeloid leukemia cells in children strain MOLM-13, as the drug of A674563 is dense
Degree increases to 3 μM from 0 μM, and the cell proportion of the G0-G1 phase of capture increases to 59.76% from 49.7%；Control TCS359,
The cell proportion of G0-G1 phase that MK2206, GSK690693 can be captured when handling cell with 1 μM is respectively as follows: 62.02%,
76.81%, 70.07% (Fig. 4 a).For acute myeloid leukemia cells in children MOLM-14, as A674563 drug concentration is from 0.3 μ
M increases to 3 μM, and the cell proportion of the G0-G1 phase of capture increases to 53.87% from 47.08%；Control TCS359, MK2206,
The cell proportion of G0-G1 phase that GSK690693 can be captured when handling cell with 1 μM is respectively as follows: 55.04%, 63.9%,
54.52% (Fig. 4 b).For acute myeloid leukemia cells in children MV-4-11, as A674563 drug concentration increases to 3 μM, capture
The cell proportion of G0-G1 phase increase to 68.69%；TCS359, MK2206, GSK690693 are compareed with energy when 1 μM of processing cell
The cell proportion of the G0-G1 phase of capture is respectively as follows: 73.62%, 64.92%, 60.48% (Fig. 4 c).Embodiment 5 proves
A674563 is to the acute myelogenous white blood for carrying FLT3 WT gene+FLT3-ITD mutated genes or FLT3-ITD mutated genes
The distribution of the cell cycle of disease cell line has a certain impact.
Claims (10)
1.A674563 is in preparation for treating in the drug for carrying the acute myelocytic leukemia patient of FLT3 mutated genes
Purposes, wherein A674563 has structure shown in following formula (I):
2. purposes according to claim 1, wherein the patient, which has, expresses caused drug resistance by FL ligand height.
3. purposes according to claim 1, wherein the FLT3 mutated genes are selected from FLT3-ITD and FLT3-
At least one of D835Y mutated genes.
4. the method that a kind of inhibition of non-treatment purpose carries the Acute Myeloid Leukemia Cells Contributing of FLT3 mutated genes, including
The cell is in contact with A674563, wherein A674563 has structure shown in following formula (I):
5. according to the method described in claim 4, wherein the acute myelocytic leukemia for carrying FLT3 mutated genes is thin
Born of the same parents are selected from one of MOLM-13, MOLM-14 and MV-4-11 or a variety of.
6. method according to claim 4 or 5, wherein the cell to be at least with concentration to 0.01 μM of A674563 phase
Contact.
In the drug of Acute Myeloid Leukemia Cells Contributing of the 7.A674563 in preparation for inhibiting to carry FLT3 mutated genes
Purposes, wherein A674563 has structure shown in following formula (I):
The drug of Acute Myeloid Leukemia Cells Contributing of the 8.A674563 in preparation for inhibiting to carry FLT3-ITD mutated genes
In purposes, wherein A674563 have following formula (I) shown in structure:
9. purposes according to claim 8, wherein the white blood of acute myeloid for carrying FLT3-ITD mutated genes
Sick cell is selected from one of MOLM-13, MOLM-14 and MV-4-11 or a variety of.
Acute Myeloid Leukemia Cells Contributing of the 10.A674563 in preparation for inhibiting carrying FLT3-D835Y mutated genes
Purposes in drug, wherein A674563 has structure shown in following formula (I):
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