CN112755188B - Application of SHMT2 inhibitor in preparation of medicines for inhibiting growth and metastasis of bladder cancer cells - Google Patents
Application of SHMT2 inhibitor in preparation of medicines for inhibiting growth and metastasis of bladder cancer cells Download PDFInfo
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Abstract
The invention provides an application of an SHMT2 inhibitor and an analogue thereof in preparing a medicament for inhibiting the growth and metastasis of tumor cells. The SHMT2 inhibitors and analogs thereof are: SHIN1, Crolibulin. In vitro studies show that the SHMT2 inhibitor and structural analogs (SHIN1 and Crolibulin) thereof can effectively inhibit the proliferation of bladder cancer cells, promote the apoptosis of bladder cancer cells, inhibit the cell cycle of bladder cancer cells, inhibit the migration of bladder cancer cells, reduce the clonogenic capacity of bladder cancer cells and inhibit the dryness maintenance of bladder cancer stem cells, so that the SHMT2 inhibitor is used for preventing and/or treating bladder cancer and can be used as a safe and effective therapeutic medicament for treating bladder cancer.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of an SHMT2 inhibitor and an analog thereof in preparation of a medicine for inhibiting growth and metastasis of tumor cells, in particular to an application of the SHMT2 inhibitor and the analog thereof in preparation of a medicine for inhibiting growth and metastasis of bladder cancer cells.
Background
Bladder cancer refers to a malignant tumor that occurs on the mucous membrane of the bladder, usually referred to as bladder urothelial cell carcinoma. Bladder cancer is the most common malignant tumor in the urinary system in China, and the incidence rate of bladder cancer is second to that of prostate cancer in the United states. The incidence of bladder cancer generally increases with age, and is much higher in men than women. Due to the industrialized development, the aging population and other reasons, the incidence of bladder cancer in China is still serious. Statistics show that the incidence of bladder cancer in both men and women, rural areas and cities in China has increased year by year in the last decade.
The occurrence of bladder cancer is a relatively complex process, associated with both environmental and genetic factors, and its pathogenesis is also complex. The treatment method is mainly based on operation, and is usually assisted by chemotherapy before and after the operation. Although the treatment methods for bladder cancer are various, the comprehensive treatment means of early surgical treatment and further radiotherapy and chemotherapy are large in harm to the body of a patient, and the prognosis is not ideal enough. Therefore, the clinical treatment of bladder cancer is urgent to find safe and effective therapeutic drugs. Research shows that the metabolic processes of tumor cells and normal cells are greatly different. The tumor cells synthesize a large amount of fatty acid, nucleotide, amino acid and other substances necessary for proliferation by regulating different metabolic pathways, and change the biosynthesis process of various biological macromolecules, so that the tumor cells are more suitable for rapid proliferation. Among the various amino acid metabolic processes, the glycine-serine metabolic pathway has been shown to be associated with the development of tumor-derived cells and tumor cells. Among them, Serine Hydroxymethyltransferase (SHMT) is a key step of intracellular Serine catabolism, catalyzing the decomposition of Serine into glycine while transferring methyl to Tetrahydrofolate (THF) to produce 5, 10-methylenetetrahydrofolate, which provides a one-carbon unit for cell growth.
SHIN1 is human serine hydroxymethyl transferase 1 and 2(SHMT1/2) inhibitor, and has IC50 values of 5 and 13nM, molecular weight of 400.47, and molecular formula C in vitro experiment24H24N4O2CAS number 2146095-85-2, structural formula as follows:
crolibulin is a structural analog of SHIN1, with a molecular weight of 417.26 and a molecular formula of C18H17BrN4O3CAS number 1000852-17-4, structural formula as follows:
no reports are available on the therapeutic effects of SHIN1 and Crolibulin on bladder cancer.
Disclosure of Invention
One of the purposes of the invention is to provide a new application of the SHMT2 inhibitor and the analogues thereof.
The invention provides a new application of a SHMT2 inhibitor and an analog thereof in preparing a medicament, which comprises the following steps: the use of SHMT2 inhibitors and analogs thereof in:
1) the application in preparing eukaryotic tumor cell proliferation inhibitor;
2) the application in preparing the medicine for inhibiting or treating tumor metastasis;
3) the application in preparing the medicine for preventing and/or treating tumor.
The application specifically includes:
a) the application in preparing the medicine for promoting the apoptosis of tumor cells;
b) the application in preparing the medicament for inhibiting the tumor cell cycle;
c) the application in preparing the medicament for inhibiting the migration of tumor cells;
e) the application in preparing the medicine for reducing the cloning and forming ability of tumor cells;
f) the application in preparing the medicine for inhibiting the dryness maintenance of the tumor stem cells;
in the above application, the eukaryote is a mammal; the tumors include bladder cancer, lung cancer and glioblastoma multiforme; in particular, the tumor is bladder cancer;
the tumor cell can be a cancer cell; in particular bladder cancer cells; the bladder cancer cell can be BIU-87, EJ, T24.
In the application, the SHMT2 inhibitor comprises a nucleic acid inhibitor, an antagonist, a down-regulator, a retarder, a blocker and the like, so long as the inhibitor can down-regulate the expression level of SHMT2 and inhibit the activity or function of serine hydroxymethyltransferase SHMT 2; they may be compounds, chemical small molecules, biomolecules; the biological molecules can be at the nucleic acid level (including DNA and RNA) or at the protein level;
in addition, there are some gene editing means capable of targeted gene editing to directionally inhibit or down-regulate gene expression, and such means and reagents may also be used in the present invention to prepare SHMT2 inhibitors.
Specifically, the SHMT2 inhibitor and analogs thereof may be: SHIN1, Crolibulin; wherein, the structural formula of SHIN1 is as follows:
the structural formula of croibulin is as follows:
another object of the present invention is to provide a eukaryotic tumor cell proliferation inhibitor or a pharmaceutical for the prevention and/or treatment of tumors,
the eukaryote is a mammal; the tumor comprises bladder cancer;
the tumor cell can be a cancer cell; in particular, it may be a bladder cancer cell.
The medicine takes an SHMT2 inhibitor or an analogue thereof as an active ingredient,
wherein the SHMT2 inhibitor is SHIN1, and its analogue is Crolibulin.
The above drugs can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The medicine prepared by taking the SHMT2 inhibitor and the structural analogue thereof as active ingredients can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
In vitro studies show that the SHMT2 inhibitor and structural analogs (SHIN1 and Crolibulin) thereof can effectively inhibit the proliferation of bladder cancer cells, promote the apoptosis of bladder cancer cells, inhibit the cell cycle of bladder cancer cells, inhibit the migration of bladder cancer cells, reduce the clonogenic capacity of bladder cancer cells and inhibit the dryness maintenance of bladder cancer stem cells, so that the SHMT2 inhibitor is used for preventing and/or treating bladder cancer and can be used as a safe and effective therapeutic medicament for treating bladder cancer.
Drawings
FIG. 1 is a graph showing the results of the effect of SHMT2 inhibitors and analogs thereof on the proliferative capacity of bladder cancer cells.
FIG. 2 is a graph showing the results of the effect of SHMT2 inhibitors and analogs thereof on apoptosis of bladder cancer cells.
FIG. 3 is a graph showing the results of the effect of SHMT2 inhibitor and its analogs on apoptosis-related proteins of bladder cancer cells.
FIG. 4 is a graph showing the results of the effect of SHMT2 inhibitors and their analogs on the cell cycle of bladder cancer.
FIG. 5 is a graph showing the results of the effect of SHMT2 inhibitors and analogs thereof on the ability of bladder cancer cells to migrate.
FIG. 6 is a graph showing the effect of SHMT2 inhibitor and its analogs on the clonality of bladder cancer cells.
FIG. 7 is a graph showing the results of the effect of SHMT2 inhibitor and its analogues on genes associated with the sternness of bladder cancer cells.
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
The SHMT2 inhibitor provided by the invention comprises a nucleic acid inhibitor, an antagonist, a down-regulator, a retarder, a blocker and the like, as long as the inhibitor can down-regulate the expression level of SHMT2 and inhibit the activity or function of serine hydroxymethyltransferase SHMT 2. They can be compounds, chemical small molecules, biomolecules. The biomolecule may be at the nucleic acid level (including DNA, RNA) or at the protein level.
In addition, there are some gene editing means capable of targeted gene editing to directionally inhibit or down-regulate gene expression, and such means and reagents may also be used in the present invention to prepare SHMT2 inhibitors.
The present invention will be further explained with reference to the following examples. The technical means used in the examples are conventional means well known to those skilled in the art and commercially available common instruments and reagents, unless otherwise specified. Reference may be made to the manufacturer's specifications for the corresponding instruments and reagents.
Examples 1,
Culturing, expanding and passaging bladder cancer cells;
BIU-87, EJ and T24 in human bladder cancer cell line are selected and grown in RPMI-1640 medium. Human kidney epithelial cell line 293T cells were grown in DMEM medium. The RPMI-1640 culture medium and the DMEM culture medium both contain penicillin (100U/ml), streptomycin (100mg/ml) and 10% fetal bovine serum. The cells were incubated at 37 ℃ in a humidified atmosphere of 5% CO 2.
Examples 2,
Cell proliferation assay
Bladder cancer cell lines BIU87, T24, EJ were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum, and human renal epithelial cell line 293T was routinely cultured in DMEM medium containing 10% fetal bovine serum. Digestion of BIU87, T24, EJ, 293T cells, 5ml PBS washing once, and accurate counting. 5000 cells/100. mu.l/well were plated in 96-well plates and cultured overnight. Following the next day of cell attachment, the cells were treated with different concentrations of Crolibulin including 0. mu.M, 1. mu.M, 10. mu.M, 20. mu.M, 30. mu.M, 40. mu.M, 50. mu.M, 60. mu.M, 70. mu.M, and SHIN1 including 0nM, 1nM, 10nM, 20nM, 30nM, 40nM, 50nM, 60nM, 70nM, RBC8 including 0. mu.M, 5. mu.M, 10. mu.M, 15. mu.M, and UCPH-101 including 0.5. mu.M, 1. mu.M, 1.5. mu.M, 2. mu.M, for 24 hours and 48 hours. At each time node, the original medium was removed, 100. mu.l of a medium containing CCK8 was added, the mixture was incubated at 37 ℃ for 2 hours, and the absorbance at 450nm (OD 450nm) was measured with a microplate reader.
FIG. 1 is a graph showing the effect of SHMT2 inhibitor (SHIN1) and its analogs (Crolibulin, RBC8, UCPH-101) on the proliferative capacity of bladder cancer cells.
From FIG. 1, it is shown that Crolibulin and SHIN1 are effective in inhibiting the proliferation of bladder cancer cells.
Examples 3,
Apoptosis assay
BIU87 cells were plated at 4X 10 per well5After the cells were seeded in 2 6-well plates and attached to the wall the next day, fresh medium containing 2. mu.l DMSO was added to 3 wells, fresh medium containing 11. mu.l MCrolidulin inhibitor was added to 3 wells, and fresh medium containing 29nM SHIN1 inhibitor was added to 3 wells and cultured for 24 hours. After 24 hours, the cell culture medium was aspirated into a suitable centrifuge tube, the adherent cells were washed once with pre-chilled PBS, and appropriate pancreatin cell digest was added to digest the cells. And (4) incubating at room temperature until the adherent cells can be blown down by gentle blowing, and sucking the digestive juice of the pancreatin cells. Excessive digestion of pancreatin is to be avoided. The collected cell culture medium was added, mixed slightly, transferred to a centrifuge tube, centrifuged at 1000rpm for 5 minutes, and the cells were pelleted. The binding buffer was diluted 1:10 with deionized water. Cells were washed twice with pre-chilled PBS and resuspended in 250. mu.l binding bufferCells, adjusted to a concentration of 1X 106Per mL; taking 100 mu l of cell suspension to put in a 5mL flow tube, and adding 5 mu l of Annexin V-FITC and 10 mu l of propidium iodide solution; mixing, and incubating at room temperature in dark for 15 min; the cells can be resuspended 2-3 times during incubation to improve staining. 400 μ l PBS was added to the reaction tube and then detected by flow cytometry, Annexin V-FITC as green fluorescence and propidium iodide as red fluorescence. The effect of croibulin and SHIN1 on apoptosis of bladder cancer cells is shown in fig. 2, and from fig. 2, it is known that croibulin and SHIN1 can promote apoptosis of bladder cancer cells.
Examples 4,
Western blot experiment for detecting apoptosis-related protein expression:
BIU87 cells were plated at 4X 10 per well the previous day5The cells were seeded in 6-well plates and after the next day of attachment, fresh medium containing 2 μ L DMSO was added to 3 wells, fresh medium containing 11 μmcrolidulin inhibitor was added to 3 wells, and fresh medium containing 29nM SHIN1 inhibitor was added to 3 wells. The culture was carried out for 24 hours. And adding a proper amount of prepared cell lysate after 24 hours, slightly blowing and beating, and collecting the lysed cells in a centrifuge tube after the cells are fully contacted with the lysate for a few seconds. Centrifuging at 10000rpm for 5 minutes, and taking the supernatant for subsequent experiments. After precooling 1 Xmembrane buffer solution while performing Tricine-SDS-PAGE electrophoresis, 6 pieces of a filter paper sheet of an appropriate size, a nitrocellulose membrane (NC membrane), were prepared. And (3) after electrophoresis, disassembling the rubber plate, removing the upper layer of concentrated gel, soaking the separation gel, the sponge, the filter paper and the NC membrane in a membrane transferring buffer solution, and fixing by using a clamp according to the sequence of the sponge-3 layers of filter paper-albumin glue-NC membrane-3 layers of filter paper-sponge. Air bubbles are not needed between every two layers, so that incomplete combination of the membrane and the protein adhesive is prevented. And (3) correctly placing the film into a wet film rotating groove according to the colors of the anode and the cathode, pouring pre-cooled film rotating buffer solution into the groove, and placing the whole device on ice. The power supply is plugged, the current is constant, 150mA, and the membrane is rotated for 1.5 hours. After the membrane transfer is finished, the membrane is carefully taken out, soaked into 1 × ponceau red solution for staining, taken out when strips exist, and rinsed in1 × TBST buffer solution for three times. The membrane was sealed in the sealing solution with tweezers and placed on a horizontal shaker for one hour. Discard blocking solution and use 1 × TBST bufferRinsing the NC membrane with the buffer solution every 5 minutes, and rinsing three times. The primary antibody was diluted 1:1000 in the antibody diluent, the membrane was placed in the antibody solution, and the shaker was placed in a freezer at 4 ℃ and incubated overnight with slow shaking. The primary antibody was recovered and the NC membrane was rinsed with 1 XTSST, buffer changed every 5 minutes and rinsed three times. The antibody was recovered and stored at-20 ℃. Diluted secondary antibody (dilution ratio 1:5000) was added and incubated for one hour at room temperature with shaking. The secondary antibody was aspirated, and the NC membrane was rinsed with 1 XTSST, buffer changed every 15 minutes, and rinsed three times. The liquid on the surface of the membrane was removed by suction with filter paper, placed in an imager, and 500. mu.L of the prepared chemiluminescent solution was added to begin photographing. As shown in FIG. 3, Caspase-3, which is an apoptosis-related protein, has been activated by generating a cleavage band, and its substrate PARP has also been cleaved to generate a cleavage band. Caspase-7 and Caspase-9 have also been activated. The experimental results further demonstrate that croibulin and SHIN1 can promote apoptosis of bladder cancer cells.
Examples 5,
Cell cycle experiments
BIU87 cells were plated at 4X 10 per well the previous day5The individual cells were seeded on 6-well plates and the serum-free medium was changed the morning after the next day of adherence to synchronize the cell cycle. After 24 hours, fresh medium containing 2 μ L DMSO was added to 3 wells, fresh medium containing 11 μmcrolibanin inhibitor was added to 3 wells, and fresh medium containing 29nM SHIN1 inhibitor was added to 3 wells. The culture was carried out for 24 hours. After 24 hours, the cell culture fluid was carefully collected into a centrifuge tube for use. Digesting the cells by pancreatin until the cells can be lightly blown down, adding the previously collected cell culture solution, blowing down all adherent cells, and collecting the adherent cells in a centrifugal tube again. The cells were pelleted by centrifugation at about 1000rpm for 5 minutes. Cells were washed twice with pre-cooled PBS. 4mL of precooled 95% ethanol is taken, 1mL of cell suspension is added dropwise while vortex shaking at a low speed (operation on ice), and after uniform mixing, the mixture is fixed for 12-24 hours at 4 ℃. The cells were pelleted by centrifugation at 1000rpm for 5 minutes. 5mL of precooled PBS was added to resuspend the cells and the cells were again pelleted by centrifugation. Gently flick the bottom of the centrifuge tube to properly disperse the cells and avoid cell clumping. 0.4mL of propidium iodide staining solution (0.4 m) was added to each tubeL staining buffer, 15. mu.L propidium iodide staining solution, 4. mu.L NaseA), slow and thoroughly resuspend the cell pellet, incubate at 37 ℃ for 30 min in the dark. The cycle was measured directly after the reaction by flow cytometry. As shown in fig. 4, two inhibitors, croibulin and SHIN1, were able to inhibit the bladder cancer cell cycle: the G1 and G2 phases were retarded, and the S phase was decreased.
Example 6
Cell migration assay
BIU87 cells were cultured in 6-well plates until the cell density reached 80%. The horizontal scoring was performed using a sterile 10 μ L tip. Cells were washed gently with PBS to remove cell debris. Three different areas of each well in a 6-well plate were selected for similar scratching and compared for the extent and distance of cell boundary migration. After 0 hours of photographing, the inhibitors 11. mu.MCrolidulin and 29nMSHIN1 were added to different wells, respectively. The scratch was again photographed 24 hours later to evaluate and calculate the speed of cell migration, and each experimental condition was repeated three times. Fig. 5 shows the effect of croibulin and SHIN1 on the migration ability of bladder cancer cells, and it can be seen from fig. 5 that, compared with the control group, the migration degree of BIU87 cells after the croibulin and SHIN1 used in the present invention are respectively treated is less than that of the control group, i.e., croibulin and SHIN1 can effectively inhibit the migration of bladder cancer cells.
Example 7,
Cell clone formation assay
The cells of each group in the logarithmic growth phase were digested with 0.25% trypsin and blown into single cells, and the cells were suspended in a medium containing 10% fetal bovine serum for use. Each group of cells was individually plated at 100 cell density per well on a dish containing 2mL of 37 ℃ prewarmed medium, 11. mu.M control in and 29nM SHIN1 were added and gently rotated to disperse the cells uniformly, and the cells were cultured in a 37 ℃ cell culture chamber with 5% CO2 and saturation humidity for 12 days. It was frequently observed that when macroscopic colonies appeared in the 6-well plate, the culture was terminated, the supernatant was discarded, carefully washed 2 times with PBS, the cells were fixed by adding a precooled methanol solution, 5mL for 15 minutes, and then the fixing solution was removed. Adding a proper amount of giemsa, dyeing for 10-30 minutes by using a dyeing solution, then slowly washing off the dyeing solution by using running water, and drying in air. The 6-well plate was photographed upside down and macroscopic clones were counted, and each experimental condition was repeated three times. As shown in FIG. 6, the control group formed more clones, but SHIN1 and Crolibulin effectively inhibited the formation of clones.
Example 8
RT-PCR experiment of related genes in dry pathway
BIU87 cells were plated in 6-well plates, and after the next day of cell attachment, equal volume of DMSO was added to the control and 11. mu.M control and 29nM SHIN1 were added to the experimental. After 24 hours of action, the cells were harvested in a 1.5mL centrifuge tube, centrifuged at 4000rpm for 3 minutes, resuspended in PBS, washed once, centrifuged at 4000rpm for 3 minutes, and the pelleted cells resuspended in Trizol for RNA extraction and reverse transcription of cDNA. The cells were resuspended in Trizol, 200. mu.L of chloroform was added, gently shaken for 15s, and allowed to stand on ice for 10 minutes. Centrifuge at 12000rpm for 15 minutes at 4 ℃ and discard the supernatant. The precipitate was gently washed by adding 1mL of 75% ethanol, centrifuged at 12000rpm for 5 minutes at 4 ℃ and the supernatant was discarded. Air-drying for 5-10 min, and adding 30 μ L preheated DEPC water for dissolving. Mu.l LOligodT and 1-2. mu.g RNA were added to the tube, and DEPC water was added to make up to 19. mu.l. Incubate at 70 ℃ for 5 minutes. Ice-bath for 10 min. The centrifuge tube was supplemented with 3. mu.L of 100mM DTT, 2.5. mu.L of 2.5mM dNTP, 6. mu.L of 5 XTRT buffer, 0.6. mu.L of LHRP (RNase inhibitor), 0.4. mu.L of MLV (reverse transcriptase). Incubate at 42 ℃ for 1 hour. Inactivation was carried out at 70 ℃ for 10 minutes. Adding the reagent, mixing, covering the cover tightly, centrifuging the centrifuge tube before incubation, and mixing uniformly. After the reaction, gel electrophoresis was performed. As can be seen in fig. 7, the expression levels of sternness related genes CTNNB1, HES1, STAT3, SMAD4 were significantly reduced in the two groups to which SHIN1 and Crolibulin were added, compared to the DMSO group. The above experiments demonstrate that the inhibitors SHIN1 and Crolibulin can inhibit the dry maintenance of bladder cancer stem cells.
Claims (2)
- The use of SHMT2 inhibitors and analogs thereof in:1) the application in preparing eukaryotic tumor cell proliferation inhibitor;2) the application in preparing the medicine for inhibiting or treating tumor metastasis;3) the application in preparing the medicament for preventing and/or treating the tumor;the eukaryote is a mammal;the tumor cell is a cancer cell;the tumor is bladder cancer; the cancer cell is a bladder cancer cell;the SHMT2 inhibitors and analogs thereof are: crolibulin.
- 2. Use according to claim 1, characterized in that: the application is as follows:a) the application in preparing the medicine for promoting the apoptosis of tumor cells;b) the application in preparing the medicament for inhibiting the tumor cell cycle;c) the application in preparing the medicament for inhibiting the migration of tumor cells;e) the application in preparing the medicine for reducing the cloning and forming ability of tumor cells;f) the application in preparing the medicine for inhibiting the dryness maintenance of the tumor stem cells;the tumor cell is a cancer cell;the cancer cell is a bladder cancer cell.
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| CN104703595A (en) * | 2012-06-01 | 2015-06-10 | 拜澳诺米克斯有限公司 | Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia |
| WO2016085990A1 (en) * | 2014-11-24 | 2016-06-02 | The Regents Of The University Of Michigan | Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity |
| US20180117010A1 (en) * | 2015-03-10 | 2018-05-03 | The Trustees Of Princeton University | SHMT Inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104703595A (en) * | 2012-06-01 | 2015-06-10 | 拜澳诺米克斯有限公司 | Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia |
| WO2016085990A1 (en) * | 2014-11-24 | 2016-06-02 | The Regents Of The University Of Michigan | Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity |
| US20180117010A1 (en) * | 2015-03-10 | 2018-05-03 | The Trustees Of Princeton University | SHMT Inhibitors |
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| Ducker et al..Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma.《PNAS》.2017,第114卷(第43期),D1. * |
| Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma;Ducker et al.;《PNAS》;20171024;第114卷(第43期);第11404页左栏第1段,第11405页右栏第2段Fig. 2A * |
| Molecular mechanism of crolibulin in complex with tubulin provides a rationale for drug design;Zhang et al.;《Biochemical and Biophysical Research Communications》;20190222;第511卷;第382页左栏第1段 * |
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| Zhang et al..Molecular mechanism of crolibulin in complex with tubulin provides a rationale for drug design.《Biochemical and Biophysical Research Communications》.2019,第511卷第382页左栏第1段. * |
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