CN103251600A - Antitumor application of 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenylpyrimidine compound - Google Patents
Antitumor application of 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenylpyrimidine compound Download PDFInfo
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Abstract
The invention discloses an antitumor application of a 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenylpyrimidine compound. Researches show that the compound is capable of doubly inhibiting TBK1 (TANK-binding kinase-1) and IKKi in a targeted manner, and has better proliferation inhibition potentials in a plurality of tumor cell strains cultured in vitro; and experiments prove that 2-amino-4-(3'-cyano-4'-pyrrolidyl)phenylpyrimidine is capable of down-regulating protein expression levels of CyclinD1, p-AKT and p-CYLD and inducing tumor cell apoptosis. Animal model tests show that the compound remarkably inhibits the growth of mouse tumors and the tumor angiogenesis, has no obvious toxic or side effect, has better anti-tumor effect and broad application prospect, and can be used for developing an anti-tumor medicament.
Description
Technical field
The invention belongs to tumor chemicals field, particularly relate to 2-amino-4-(3 '-cyano group-4 '-pyrrolidinyl) antitumor of phenyl pyrimidine chemical compound uses.
Background technology
Chemotherapy is the important means of cancer clinical treatment, and chemotherapeutics reaches therapeutic effect by division growth, the promotion cell differentiation of direct kill tumor cell or inhibition tumor cell.Seek active and effective prevention and seem very urgent and necessary by way of reaching effective medicine, the particularly application of molecular targeted treatment in oncotherapy, seek effective, special inhibition means and inquire into its mechanism of action, not only be conducive to the generation of prophylaxis of cancer, can also provide new approach for clinical treatment.
In recent years, people find other two kinds of non-classical I kappa b kinases (IKKs)---TBK1 and IKKi gradually, they are important derivants that body starts the interferon signal path when being subjected to viral infection, after Toll sample receptor is activated by virus composition, TBK1 and IKKi and TRAF3, TANK assembling, further (IRF 3 at a plurality of serines and threonine residues site phosphorylation interferon regulatory factor, 7), IRF-3 and IRF-7 dimerization, go into nuclear and induce the expression of multiple antiviral genes such as interferon type gene, thereby activate the innate immunity approach.Except the role in the antiviral immunity reaction, non-classical IKKs also participates in other signal paths, for example tumor generation etc.It is reported in some transformant that the TBK1 kinase activity raises and be that these transformants existence are necessary.Suppress the apoptosis that the expression of TBK1 can inducing tumor cell by the RNAi technology, yet the epithelial cell of non-tumor source property does not but rely on TBK1 and survives.There is genomics to studies show that IKKi is the oncogene of human breast carcinoma, and in human breast cancer cell, suppresses IKKi and can induce breast cancer cell death.Thereby TBK1 and IKKi have caused people's attention gradually in oncology.
Originally discover that in same tumor TBK1 and IKKi are not high expressed or intrinsic state of activation simultaneously, suppress one of them expression and can activate another kinases.Therefore, because eclipsing effects and compensation between this two kinds of kinases, simple inhibition TBK1 or IKKi all can not effectively suppress growth of tumour cell, this can effectively suppress tumor cell proliferation yet ought suppress these two kinds of kinases simultaneously, thereby has pointed out it may become a good target spot for the treatment of tumor.
Summary of the invention
The present invention aim to provide a kind of 2-amino-4-(3 '-cyano group-4 '-pyrrolidinyl) anticancer usage of phenyl pyrimidine chemical compound, for development of new targeting from now on suppresses TBK1 and the IKKi antitumor drug is expanded new thinking and method.
In order to achieve the above object, technical scheme provided by the invention is:
The invention provides a kind of have 2-amino-4-(3 '-cyano group-4 of suppressing TBK1 and IKKi '-pyrrolidinyl) the phenyl pyrimidine chemical compound, in this description, this chemical compound abbreviates CMPD as, the CMPD structural formula is as follows, its association attributes is as shown in the table.
Structural formula of compound
2-amino-4-(3 '-cyano group-4 '-pyrrolidinyl) association attributes of phenyl pyrimidine
The present invention has disclosed Compound C MPD and has had the mechanism of passing through to suppress TBK1 and IKKi inducing apoptosis of tumour cell, and has found that CMPD is by suppressing the effect of TBK1 and IKKi anti-tumor in vivo.Discover through the present invention, have eclipsing effects and compensation between these two kinds of kinases of TBK1 and IKKi, simple inhibition TBK1 or IKKi all can not effectively suppress growth of tumour cell, this can effectively suppress tumor cell proliferation yet ought suppress these two kinds of kinases simultaneously, Compound C MPD then can suppress these two kinds of kinases simultaneously, thereby becomes the treatment target spot of new type antineoplastic medicine.
The present invention has also verified the antitumor curative effect of Compound C MPD by animal model, CMPD can successfully suppress the growth of carcinoma of tongue tumor bearing nude mice and carcinoma of prostate FVB mouse interior tumor by TBK1 and IKKi double inhibition, and the mice body is not had obvious toxicity, side effect.The antitumor action of this chemical compound activates with suppressing AKT, the downward modulation vegf expression, and it is relevant to suppress tumor-blood-vessel growth.The present invention for from now on further the development of new targeting clinical medicine that suppresses TBK1 and IKKi lay the foundation.
Description of drawings
Fig. 1 is that TBK1 and IKKi express in kinds of tumor cells and the activation situation in the embodiment of the invention 1.
Fig. 2 is the IKKi of IKKi-siRNA SCC-25 cell and matched group in the embodiment of the invention 1, p-TBK1, the protein expression level of TBK1.
Fig. 3 be in the embodiment of the invention 1 among people's carcinoma of tongue cell SCC-25 siRNA suppress TBK1 or/and its cell proliferation level after the IKKi.(* * P＜0.01 difference has statistical significance, and the siRNA jamming effectiveness adopts Western blotting checking).
Fig. 4 be in the embodiment of the invention 2 the RAW264.7 cell with LPS(1 μ g/ml) handle the protein expression level of IRF-3 and p-IRF-3 behind the different time.
Fig. 5 handle behind 1 hr with the CMPD of variable concentrations for RAW264.7 cell in the embodiment of the invention 2 and with LPS(1 μ g/ml) IRF-3 of stimulation 1 hr and the protein expression level of p-IRF-3.
Fig. 6 is CMPD(1.0 μ M under the inverted phase contrast microscope in the embodiment of the invention 3) cellular morphology of handling the SCC-9 cell of different time length changes (a: contrast; B:24 hr; C:48 hr; D:72 hr) (enlargement ratio 200 *).
Fig. 7 for SCC-9 cell in the embodiment of the invention 3 at CMPD(1.0 μ M) handle behind 72 hr and untreated fish group comparison diagram (red-label is apoptotic cell among the figure, and blue markings is nucleus).
Fig. 8 be in the embodiment of the invention 3 the SCC-9 cell at CMPD(1.0 μ M) different time handles back related apoptosis protein expression level.
Fig. 9 is SCC-9 cell related apoptosis protein expression level after the CMPD of variable concentrations handles 24 hr in the embodiment of the invention 3.
Figure 10 be in the embodiment of the invention 3 the SCC-9 cell at CMPD(1.0 μ M) handle different time and handle back Cyclin D1 protein expression level.
Figure 11 is SCC-9 cell in the embodiment of the invention 3 AKT and phosphorylated protein (S473, T308) expression after the CMPD of variable concentrations handles 30 min.
Figure 12 be in the embodiment of the invention 3 the SCC-9 cell at CMPD(1.0 μ M) handle p-CYLD protein expression level behind 1 hr.
Figure 13 be when experiment finishes in the embodiment of the invention 4 in nude mice outward appearance photo and the art tumor dissect photo.
Figure 14 is the gross tumor volume variation of CMPD treatment carcinoma of tongue SCC-9 cell tumor bearing nude mice in the embodiment of the invention 4 and tests tumor weight and tumor photo (* P＜0.05 when finishing; * P＜0.01).
Figure 15 is the gross tumor volume variation of CMPD treatment carcinoma of prostate Myc-CaP cell lotus tumor FVB mice in the embodiment of the invention 4 and tests tumor weight and tumor photo (* P＜0.05 when finishing; * P＜0.01).
Figure 16 is that immunohistochemistry detects VEGF and the expression (enlargement ratio 400 *) of p-AKT in matched group and experimental group nude mice tumor tissues in the embodiment of the invention 4.
Figure 17 is that nude mice tumor tissues RT-PCR detects VEGF gene expression dose (n=3) in the embodiment of the invention 4.
Figure 18 is that nude mice tumor tissues Western blotting detects p-AKT protein expression level (n=3) in the embodiment of the invention 4.
The specific embodiment
Choose ten kinds of tumor cell lines, comprise carcinoma of tongue cell strain (SCC-9, SCC-15, SCC-25), prostate gland cancer cell strain (PC3, DU145, LNCaP, Myc-CaP), (T-47D) albumen is extracted in the conventional back of cultivating to breast carcinoma cell strain for MCF-7, MDA-MB-231, Western blotting measures the protein content of its TBK1, P-TBK1, IKKi, P-IKKi, and β-actin is confidential reference items (Fig. 1).
Found that TBK1 and IKKi all have expression in tumor cell, as seen the phosphorylation level of IKKi all expresses in various tumor cells, but it is inconsistent that the phosphorylation level of TBK1 is expressed in different tumor cells, even at carcinoma of tongue cell strain (SCC-9, SCC-15 is difficult to detect p-TBK1 in SCC-25) and expresses.But express (Fig. 2) when in the SCC-25 cell, adopting the siRNA technology to suppress its IKKi, Western blotting found that the expression of the TBK1 among the SCC-25 that IKKi-siRNA handles is better than matched group SCC-25 cell, and the expression of its P-TBK1 simultaneously also obviously strengthens.Therefore illustrate that TBK1 and IKKi express and activate in tumor cell, suppress IKKi merely and can cause the compensatory activation of TBK1.
And then adopt siRNA to suppress TBK1 or/and IKKi can obtain con-siRNA, TBK1-siRNA, IKKi-siRNA and TBK1﹠amp to carcinoma of tongue cell SCC-25; Four groups of IKKi-siRNA SCC-25, the conventional cultivation 5 days respectively the 0th, 1, carried out cell counting in 3,5 days, was depicted as broken line graph (Fig. 3).TBK1-siRNA, the propagation level of two groups of cells of IKKi-siRNA SCC-25 slightly descends with respect to matched group, but their difference and not statistically significant between three groups (P〉0.05), but its propagation level is suppressed significantly after the TBK1 of SCC-25 and IKKi all are suppressed, and difference has statistical significance (P＜0.01) between its excess-three group.The expression that this explanation siRNA technology suppresses TBK1 or IKKi separately can not effectively suppress the carcinoma of tongue cell proliferation, suppresses the propagation that its both expression then can effectively suppress the carcinoma of tongue cell when simultaneously.
Therefore embodiment shows, TBK1 and IKKi be high expressed and activation in tumor cell, suppresses the propagation that they can effectively suppress tumor cell simultaneously, shows that TBK1 and IKKi can become the molecular target of new type antineoplastic medicine.
The inhibition ability of the TBK1 of embodiment 2, CMPD and IKKi and anti tumor activity in vitro evaluation experimental
Can phosphorylation IFN regulatory factor 3 and 7 (IRF-3/IRF-7) TBK1 and IKKi mainly come from it and activate in immunne response after, LPS can activate TBK1 and IKKi phosphorylation IRF-3 in the RAW264.7 cell, thereby the inhibition situation of TBK1 and IKKi activity can detect by Western blotting in the RAW264.7 cell.If these two kinds of kinase whose activity are blocked, the phosphorylation level of IRF-3 will reduce or disappear, and the p-IRF-3 band just can embody chemical compound indirectly to these two kinds kinase whose inhibition abilities.
Fig. 4 is presented at that LPS refers to lipopolysaccharide in this description of LPS() effect down, p-IRF-3 expresses gradually and strengthens, and is the highest at 1 hr, reduces afterwards, is difficult to detect when 4 hr.Having obtained the p-IRF-3 optimal detection condition is that LPS stimulates 1 hr.Thereby to the RAW264.7 cell handle behind 1 hr with the CMPD of variable concentrations and with LPS(1 μ g/ml) stimulate 1 hr, Western blotting detects the inhibition ability (Fig. 5) that the protein expression level of respectively organizing IRF-3 and p-IRF-3 is analyzed its TBK1 and IKKi, under variable concentrations CMPD effect, all can reduce the phosphorylation level of IRF-3, under 0.5 μ M effect, just can reduce the phosphorylation level of IRF-3 effectively, and when 1.0 μ M, almost can't detect p-IRF-3, so can think that this chemical compound has the inhibition ability of TBK1 and IKKi relatively preferably.
Use CPMD effect 72 hr of gradient concentration in various tumor cell lines respectively, in isocyatic this description of DMSO(, DMSO refers to dimethyl sulfoxide) be made as contrast, mtt assay detects proliferative activity.Can calculate IC50 value (the IC50 value refers to suppress the drug level value of cell proliferation 50%) according to above MTT result.Generally speaking, IC50 is more low, and the antitumor action of chemical compound is more strong.Compound C MPD has at selected tumor cell line and suppresses proliferation function preferably, and it is lower to show as its IC50, all at micromole's order of magnitude (0.584-1.872 μ M), as shown in table 1, shows higher anti-tumour cell proliferative activity.
Table 1Compound C MPD is to the IC50 of various tumor cell in-vitro multiplications
| Tumor cell line | IC50 (μM) |
| SCC-9 | 0.800 |
| SCC-15 | 0.645 |
| SCC-25 | 0.678 |
| PC3 | 0.667 |
| DU145 | 0.584 |
| LNCaP | 0.584 |
| Myc-CaP | 0.601 |
| MCF-7 | 0.899 |
| MDA-MB-231 | 1.872 |
| T-47D | 0.876 |
Therefore embodiment 2 shows that this TBK1 of CMPD and IKKi double inhibition chemical compound have pharmacy attribute preferably, can be used as the candidate compound of new type antineoplastic medicine, and it all has the effect of obvious inhibition propagation to selected tumor cell.
To the SCC-9 cell with CMPD(1.0 μ M) handle, preceding to handling, handle back 24 hr, handle back 48 hr and handle back 72hr and carry out observing and take pictures (Fig. 6) under the mirror, SCC-9 cell attachment growth before handling, cellular morphology is polygon or oval, be evenly distributed, cell stretches and is connected to each other.After acting on 24 hr, the parts of fine intercellular connects fracture, and the cellular morphology systematicness reduces, and fusiformis and similar not too regular triangle are arranged; After acting on 48 hr, wide crack appears between attached cell, part cell cell rounding, and volume-diminished, soft edge is unintelligible, and the part cell membrane is the bulging of vesicle shape, and the part cell detachment suspends; After acting on 72 hr, it is more that cell detachment suspends, the attached cell rareness, and cell is irregular, and is not of uniform size, even is cracked into fragment.This phenomenon shows that along with prolong action time, CMPD has induced the apoptosis of carcinoma of tongue cell SCC-9.
Further use ApopTag original position apoptosis detection kit the SCC-9 cell routine is cultivated 72 hr and with Compound C MPD(1.0 μ M) the SCC-9 cell handled these two groups of cells of 72 hr detect (Fig. 7).Every picture group sheet has three figure, and first (DAPI) Smalt partly is location nucleus, i.e. all cells; Apoptotic cells takes place in red part location in second (ApoTag); The 3rd (Merge) is by first and second opening and closing and forms, can observe all cells simultaneously and apoptotic cells takes place.Therefore, the ratio of matched group apoptotic cell is starkly lower than the CMPD processed group among the figure; On the other hand, the simple photo of observing DAPI dyeing can find that the blue portion of CMPD processed group presents ellipse unlike matched group, but irregular, lamellar distribution, this means that CMPD handles the nuclear DNA in back and fragmentation occurred, blue portion quantity is also few than matched group, and this has illustrated that CMPD handles back cell proliferation speed also less than matched group.The result that this has also verified front morphological observation and last chapter ganglion cell proliferation experiment gained illustrates that again CMPD can promote the carcinoma of tongue apoptosis, has suppressed its propagation.
Use CMPD(1.0 μ M respectively) gradient time treatment S CC-9 cell (Fig. 8), and use the SCC-9 cell of CMPD of gradient concentration to handle 24 hr(Fig. 9), Western blotting detects relevant Caspase family protein and PARP activation situation.The result is presented under the same CMPD concentration along with the growth in processing time, and Cleaved Caspase-9, Cleaved Caspase-3, Cleaved Caspase-7 and Cleaved PARP protein expression level strengthen gradually; The same processing time along with the increasing of CMPD concentration, its apoptosis-related protein expression is same variation tendency.Illustrate that CMPD induces the carcinoma of tongue apoptosis, is time and dose dependent.
With CMPD(1.0 μ M) carcinoma of tongue SCC-9 cell is carried out the processing of gradient time, Western blotting detects the expression (Figure 10) of Cyclin D1 albumen, and the result shows growth action time along with CMPD, and Cyclin D1 expresses decline.
CMPD effect SCC-9 30 min with gradient concentration, Western blotting detects the expression (Figure 11) of AKT and phosphorylated protein thereof, the result shows along with CMPD concentration increases, the phosphorylation level in two sites of AKT descends, be dose dependent, show that this TBK1 and IKKi double inhibition chemical compound can suppress the activation of AKT.
With CMPD(1.0 μ M) handle carcinoma of tongue SCC-9 cell 1 hr, Western blotting detects the expression (Figure 12) of p-CYLD albumen, and the result shows that CMPD handles its p-CYLD expression of back reduction is all arranged.
Therefore this example confirms, CMPD has double inhibition TBK1 and IKKi function, can induce the carcinoma of tongue apoptosis, and presentative time and dose dependent, and its mechanism is relevant with the protein expression of downward modulation carcinoma of tongue cell Cyclin D1, p-AKT, p-CYLD.
Have double inhibition TBK1 and IKKi extracorporeal anti-tumor ability of cell proliferation based on Compound C MPD, adopt bearing mouse model to verify the ability of its antitumor propagation.
Tumor cell line adopts carcinoma of tongue cell SCC-9, purchase in US mode culture collection warehousing (American type culture collection, ATCC) and prostate cancer cell line Myc-CaP, separate from a kind of c-Myc transgenic carcinoma of prostate mice, it can grow tumor in having the FVB mice body of immunity.
15 of the congenital cellular immunity deficiency Nu/Nu nude mouses of BALB/C are selected in the carcinoma of tongue zoopery for use, and are female, 8 ages in week, body weight 22-24 g, SPF(Special pathogen free) level.12 FVB mices are adopted in the zoopery of Myc-CaP carcinoma of prostate.All animals are arrived at the back and isolate cage tool lamina air flow purification indoor feeding in aseptic independent air-supply, keep constant temperature (26-28 ℃), constant humidity (relative humidity 40%-60%), and 12 hr light and shades are switched.Feedstuff, drinking-water, bedding and padding all use after sterilization treatment.Experiment, feeding process all reach the SPF condition.
(1) with CMPD treatment carcinoma of tongue SCC-9 cell tumor bearing nude mice.
(1) collects the preparation cell
Choose exponential phase SCC-9 cell, digestion, centrifugal collecting cell, PBS washing 2 times, the microscopically counting, and add an amount of Matrigel, adjusting final concentration of cells is 2.0 * 107/ml cell suspension standby (operation on ice keeps low temperature).
(2) inoculation animal
After nude mice is arrived at reception, in order to allow nude mice adapt to new environment, regulate state, about week, record life and the health of nude mice at animal center breeding observing l earlier.Wait for nude mice diet, movable normal and do not have and experimentize after excitation is levied.In superclean bench, routine disinfection nude mice left side nape portion skin accurately extracts cell suspension 0.5 ml(with l ml asepsis injector and namely contains 1 * 107 in SCC-9 cell) inject nude mice on the left of nape portion subcutaneous, point of puncture is about 1 cm apart from the injection site.Send nude mice back to former rearging cage after the inoculation, observe and record diet, spirit and the defecation situation of nude mice.
(3) grouping and treatment
After inoculating 24 hr, 15 nude mices are divided into 2 groups at random, 5 of matched groups, 10 of experimental grouies.Treatment group every day (identical time point) is to nude mice abdominal cavity injection CMPD solution, dosage is that (nude mice as 20 mg needs 2 mg chemical compounds to 100 mg/kg body weight, namely injecting 200 ul Compound C MPD solution (1 mg/100 ul) gets final product), treatment is 34 days continuously, matched group (with the same time point of experimental group) injecting normal saline is (the nude mice direct injection 200 ul normal saline of 20 mg) in contrast, and two groups of nude mices are finished treatment simultaneously.
(2) with CMPD treatment carcinoma of prostate Myc-CaP cell lotus tumor FVB mice
(1) collects the preparation cell
Choose exponential phase Myc-CaP cell, digestion, centrifugal collecting cell, PBS washing 2 times, the microscopically counting, and add an amount of Matrigel, adjusting final concentration of cells is 6.0 * 106/ml cell suspension standby (operation on ice keeps low temperature).
(2) inoculation animal
Raising condition such as above-mentioned, in superclean bench, routine disinfection FVB left side nape portion skin accurately extracts cell suspension 0.5 ml(with l ml asepsis injector and namely contains 3.0 * 106 in Myc-CaP cell) inject mice on the left of nape portion subcutaneous, point of puncture is about 1 cm apart from the injection site.Send mice back to former rearging cage after the inoculation, observe and record diet, spirit and the defecation situation of mice.
(3) grouping and treatment
After inoculating 24 hr, 12 FVB mices are divided into 2 groups at random, 6 of experimental grouies, 6 of matched groups.Treatment group every day (identical time point) is to mouse peritoneal injection CMPD solution, dosage is 100 mg/kg body weight, treatment is 18 days continuously, matched group (with the same time point of experimental group) injecting normal saline is (the nude mice direct injection 200 ul normal saline of 20 mg) in contrast, and two groups of FVB mices are finished treatment simultaneously.
The curative effect assessment
The conventional raising observed diet, the activity of mice every day, surveys the mice body weight in per three days, and with the major diameter (L) of vernier caliper measurement tumor, minor axis (W), and record.Its gross tumor volume computational methods are the face formula as follows: square (W2)/2 of tumor volume (V)=tumor major diameter (L) * tumor minor axis.
The zoopery result
Two groups of tumor cell inoculations are behind mice, and small embossment appears in its injection site, are the tumor tuberosity, are not too regular circular, and the air spots that has is smooth.It is very fast that the matched group tumor is growth, centered by the initial injection position, soaks into towards periphery gradually, and volume increases gradually, and the quality of touching is harder.Minority tumor center occurs downright bad, depression or incrustation phenomenon; The experimental group tumor growth is slow, and volume is less than matched group.Along with the chemical compound lumbar injection time increases, its inhibition to the experimental group tumor growth is obvious gradually in the experimentation.
Put to death whole mices when experiment finishes, anatomical isolation goes out tumor, has more blood vessel to grow into around the visible matched group tumor in the art, and tumor body colour pool is ruddy; And experimental group tumor peripheral vessels is tiny, sparse, tumor body color light partially (Figure 13).All the picture of tumor is seen Figure 14 and Figure 15, and the matched group tumor is obviously greater than experimental group, and growth of tumor is suppressed under the intervention of CMPD in the illustrative experiment group.
The CMPD toxicity assessment: the mice body weight that participates in experiment when experiment beginning and end there is no notable difference.In the therapeutic process, the mice mental status is good, and growth promoter, diet activity show no obvious abnormalities, and shows that CMPD does not have obvious toxicity, side effect.
Fresh nude mice tumor tissues is carried out frozen section, and carry out immunohistochemistry, images acquired is seen Figure 16.VEGF refers to VEGF in this description of VEGF() mainly in endochylema, to express, positive particle is pale brown color, wherein is strongly expressed in the matched group, is weak expression in the experimental group.P-AKT then all has expression in nucleus and endochylema, wherein all be strongly expressed in the matched group in nucleus and the endochylema, is weak expression (Figure 16) in the experimental group in nucleus and the endochylema.Shown that CMPD treats the nude mice carcinoma of tongue and can reduce its VEGF and p-AKT.
RT-PCR detects the gene expression dose (Figure 17) of VEGF in the nude mice tumor tissues, and the result shows gene expression dose obviously downward modulation in the experimental group that CMPD handles of VEGF, and this result is consistent with the immunohistochemical analysis result of front.
Western blotting detects the protein expression level (Figure 18) of nude mice tumor tissues p-AKT, the result shows protein expression level obviously downward modulation in the experimental group that CMPD handles of p-AKT, and Western blotting analysis result is consistent with the immunohistochemical analysis result of front.
Therefore this example confirms, this TBK1 of CMPD and IKKi double inhibition chemical compound can successfully suppress the growth of carcinoma of tongue tumor bearing nude mice and carcinoma of prostate FVB mouse interior tumor, and the mice body is not had obvious toxicity, side effect.The antitumor action of CMPD activates with suppressing AKT, the downward modulation vegf expression, and it is relevant to suppress tumor-blood-vessel growth.
Claims (5)
1.2-amino-4-(3 '-cyano group-4 '-pyrrolidinyl) antitumor of phenyl pyrimidine chemical compound is used, the structural formula of described chemical compound is:
, it is characterized in that this chemical compound is for the preparation of the medicine that suppresses TBK1 and two kinds of kinase activities of IKKi simultaneously.
2. the antitumor of chemical compound as claimed in claim 1 is used, and it is characterized in that: described chemical compound is for the preparation of the broad-spectrum anti-tumor medicine.
3. the antitumor of chemical compound as claimed in claim 2 is used, and it is characterized in that: described chemical compound is for the preparation of suppressing tumor-blood-vessel growth class medicine.
4. the antitumor of chemical compound as claimed in claim 2 is used, and it is characterized in that: described chemical compound is for the preparation of anti-carcinoma of tongue medicine.
5. the antitumor of chemical compound as claimed in claim 2 is used, and it is characterized in that: described chemical compound is for the preparation of anti-carcinoma of prostate medicine.
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| WO2017102091A1 (en) | 2015-12-18 | 2017-06-22 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| WO2017207534A1 (en) | 2016-06-03 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituted heteroarylbenzimidazole compounds |
| US10040781B2 (en) | 2014-09-26 | 2018-08-07 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10072001B2 (en) | 2014-06-03 | 2018-09-11 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10316049B2 (en) | 2015-12-17 | 2019-06-11 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
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| WO2008032086A1 (en) * | 2006-09-14 | 2008-03-20 | Astrazeneca Ab | 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders |
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| WO2008032086A1 (en) * | 2006-09-14 | 2008-03-20 | Astrazeneca Ab | 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10072001B2 (en) | 2014-06-03 | 2018-09-11 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10259811B2 (en) | 2014-06-03 | 2019-04-16 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10040781B2 (en) | 2014-09-26 | 2018-08-07 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10253019B2 (en) | 2014-09-26 | 2019-04-09 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| US10316049B2 (en) | 2015-12-17 | 2019-06-11 | Gilead Sciences, Inc. | Tank-binding kinase inhibitor compounds |
| WO2017102091A1 (en) | 2015-12-18 | 2017-06-22 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| US10894784B2 (en) | 2015-12-18 | 2021-01-19 | Bayer Pharma Aktiengesellschaft | Heteroarylbenzimidazole compounds |
| WO2017207534A1 (en) | 2016-06-03 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituted heteroarylbenzimidazole compounds |
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