CN114380812A - BCR/ABL tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia - Google Patents

BCR/ABL tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia Download PDF

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CN114380812A
CN114380812A CN202011135706.0A CN202011135706A CN114380812A CN 114380812 A CN114380812 A CN 114380812A CN 202011135706 A CN202011135706 A CN 202011135706A CN 114380812 A CN114380812 A CN 114380812A
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李加忠
黄婷婷
王欣
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Lanzhou University
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Abstract

The invention discloses a BCR/ABL tyrosine kinase inhibitor for treating chronic granulocytic leukemia, and discloses a compound for inhibiting BCR/ABL tyrosine kinase, wherein the compound is prepared by constructing a pharmacophore model based on a known BCR/ABL tyrosine kinase inhibitor, virtually screening a database, optimizing the structure of a compound with the best activity, and finding that the optimized compound can effectively inhibit the phosphorylation of BCR/ABL tyrosine kinase, inhibit the proliferation of imatinib-resistant and drug-intolerant cells, and induce cycle arrest, autophagy and apoptosis of imatinib-resistant and drug-intolerant cells. The compound disclosed by the invention is used as a BCR/ABL tyrosine kinase inhibitor, and provides a new choice for treating chronic granulocytic leukemia.

Description

BCR/ABL tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia
Technical Field
The invention relates to a compound obtained by computer virtual screening, in particular to a BCR/ABL tyrosine kinase inhibitor for treating chronic granulocytic leukemia.
Background
Chronic Myelogenous Leukemia (CML) is a hematologic malignancy transformed from hematopoietic stem cells, marked by the Ph chromosome, discovered by Nowell and Hungerford in 1960. The Ph chromosome is the result of translocation Nos. 9 (ABL) and 22 (BCR), resulting in the BCR/ABL fusion gene (A new coherent chromosomal aberration in bacterial biology leucoderma identified by y genetic mutation and Giemsa stabilization. Rowley JD. Nature 1973; 243: 290-3.). BCR/ABL fusion genes cause deregulation of tyrosine kinase activity, and deregulation of BCR/ABL tyrosine kinase activity is the major causative agent of CML (Targeted drugs in cyclic mileid leukemia. leukamia. Gora Tybor, J.; Robak, T.. Current medical Chemistry 2008,15,3036-51.), leading to cell proliferation, survival and anti-apoptosis.
Imatinib, a small molecule that binds to and inhibits the activity of the BCR/ABL kinase domain, is the first generation of BCR/ABL tyrosine kinase inhibitors, and is the first line therapeutic for CML, but 70% of CML patients relapse in advanced disease due to drug resistance. The reasons for the drug resistance of imatinib include point mutation of BCR/ABL structural domain, amplification of BCR/ABL protein, high expression of BCR/ABL protein and over-expression of drug-resistant P glycoprotein. The main reason for imatinib tolerance is mutation of the BCR/ABL kinase domain, which interferes with the binding of imatinib to the BCR/ABL domain, of which mutation the T315I mutation is most common. Dasatinib is a second-generation tyrosine kinase inhibitor that has been approved by the FDA for the treatment of CML, but has the risk of causing rare diseases-pulmonary hypertension. Therefore, a novel inhibitor targeting BCR/ABL tyrosine kinase is searched, and T315I can be antagonized, which has important significance for CML treatment.
Disclosure of Invention
The invention aims to provide an inhibitor targeting BCR/ABL tyrosine kinase and capable of inducing T315I mutant cell apoptosis. The technical scheme of the invention is as follows:
a compound of the structural general formula (I) of a targeting BCR-ABL tyrosine kinase or the forms of tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof:
Figure BDA0002736543140000011
Figure BDA0002736543140000021
wherein: r1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl;
R3: is selected from
Figure BDA0002736543140000022
Or an alkyl group.
Preferably, the substituent R3 of said compound of formula (I) is substituted to give the following formula:
Figure BDA0002736543140000023
wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl;
R4selected from methyl, hydrogen,
Figure BDA0002736543140000024
Figure BDA0002736543140000025
Wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl;
R5is selected from
Figure BDA0002736543140000026
Figure BDA0002736543140000027
Figure BDA0002736543140000031
Wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl; r6Is ethyl;
Figure BDA0002736543140000032
wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl; r7Selected from methyl or
Figure BDA0002736543140000033
Preferably, the compound of formula (ii) is selected from:
Figure BDA0002736543140000034
Figure BDA0002736543140000041
preferably, the compound of formula (iii) is selected from:
Figure BDA0002736543140000051
Figure BDA0002736543140000061
Figure BDA0002736543140000071
Figure BDA0002736543140000081
Figure BDA0002736543140000091
preferably, the compound of formula (iv) is selected from:
Figure BDA0002736543140000092
preferably, the compound of formula (v) is selected from:
Figure BDA0002736543140000093
a second object of the present invention is to provide a pharmaceutical composition, characterized in that it contains a therapeutically effective amount of said compound or its tautomers, meso-isomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The third purpose of the invention is to provide the application of the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer and the mixture form thereof, and the medicinal salt thereof in inhibiting BCR/ABL tyrosine kinase.
The fourth purpose of the invention is to provide the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer and the mixture form thereof, and the application of the medicinal salt thereof in antagonizing the T315I mutation.
The fifth purpose of the invention is to provide the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer and the mixture form thereof, and the pharmaceutically acceptable salt thereof, and the application of the compound in preparing the medicament for preventing or treating the leukemia.
Preferably, the leukemia is chronic myeloid leukemia.
The invention has the beneficial effects that: the screened compounds are verified by a cytotoxicity experiment through virtual screening, the compounds with better activity are optimized in structure, and are screened again, and the compounds are verified by a biological experiment, so that the compound can inhibit the proliferation of leukemia Imatinib drug-resistant and drug-intolerant cells, and particularly, the effect of the compound is nearly 10 times stronger than that of Imatinib in inhibiting the proliferation of BaF3/T315I Imatinib drug-intolerant cells. Through flow experiments, the compound induces cell cycle arrest at G for K562 cells2In the case of BaF3/WT and BaF3/T315I, compounds induced cell cycle arrest at G1And (4) period. Through flow experiments and western blot experiments, the compounds are found to be capable of inducing autophagy and apoptosis of cells, inhibiting the expression of BCR/ABL tyrosine kinase protein, hopefully becoming potential BCR/ABL inhibitors and providing a new choice for CML treatment.
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FIG. 1: the Hypogen1 model, which is the best scoring among Hypogen pharmacophores, includes one hydrogen bond acceptor, four hydrophobic centers. FIG. 2: the hipop 1 model with the best scoring value in the hipop pharmacophore included two aromatic ring centers, three hydrophobic centers, one hydrogen bond donor, two hydrogen bond acceptors.
FIG. 3: the structural general formula of the BCR-ABL tyrosine kinase inhibitor compound obtained by screening.
FIG. 4: MTT results of K562, BaF3/WT, BaF3/T315I cells treated with structurally optimized compounds at different concentrations and positive control drug Imatinib for 72 h.
FIG. 5: the compound ZINC21710815 at different concentrations acts on the cell cycle effects of K562, BaF3/WT and BaF3/T315I cells for 24 h.
FIG. 6: the effect of varying concentrations of compound ZINC21710815 on K562, BaF3/WT and BaF3/T315I cells for 24h on apoptosis and on BaF3/WT and BaF3/T315I cells for 48h on the apoptotic protein Caspase-3. FIG. 7: effect of different concentrations of compound ZINC21710815 on BaF3/WT and BaF3/T315I cells for 48h on autophagy-related proteins LC3 and Beclin 1.
FIG. 8: the influence of different concentrations of compound ZINC21710815 and positive control drug Imatinib on BaF3/WT cells for 48h on BCR/ABL targets and their downstream proteins p-STAT5 and p-Crkl.
Detailed Description
The following examples are intended to further illustrate the scope of the invention, but are not intended to limit the scope of the invention.
The invention aims to screen an inhibitor targeting BCR/ABL tyrosine kinase by a computer and induce T315I mutant cell apoptosis.
The screening process for compounds targeting BCR/ABL tyrosine kinase comprises the following steps: (1) collecting known inhibitors targeting BCR/ABL tyrosine kinase, (2) establishing a pharmacophore model, (3) verifying the pharmacophore model, (4) screening a database by using the pharmacophore model, (5) carrying out drug-like property, ADMET and docking screening, (6) carrying out cytotoxicity experiments, (7) optimizing the structure, and (8) carrying out biological experiment verification.
The construction of the pharmacophore model of the invention: collecting known targeting BCR/ABL tyrosine kinase inhibitors obtained from the literature, selecting pharmacophore characteristic elements, and constructing Hypogen and Hiphop pharmacophores.
The verification of the pharmacophore model of the invention:
selecting a Hypogen pharmacophore model with the best score, collecting known targeting BCR/ABL tyrosine kinase inhibitors obtained from the literature as a test set, verifying the capability of the pharmacophore model for predicting activity, verifying the reliability of the model by a Fischer random verification method, and verifying the hit capability of the model by a Decoy set method.
The highest scoring value hipop pharmacophore model is selected, known targeting BCR/ABL tyrosine kinase inhibitors obtained from the literature are collected as a test set, and the hit capability of the pharmacophore model is verified.
The relevant physicochemical properties comprise:
calculating the physicochemical properties of the compound, including the Number of Hydrogen Bond Acceptors (HBA), the Number of Hydrogen Bond Donors (HBD), the lipid-water partition coefficient (logP), and the Molecular Weight (MW);
simulating the properties of absorption, distribution, metabolism, excretion and toxicity of the compound in an organism, and the like, including predicting the intestinal absorption property, water solubility and blood brain barrier permeability of the compound;
binding energy of the compound and the receptor protein is predicted by docking.
Example 1: generation of Hypogen pharmacophore model
22 known BCR/ABL tyrosine kinase inhibitors were selected as the training set of the hydrogen pharmacophore model, hydrogen-bond acceptor (HBA), hydrogen-bond donor (HBD), hydrophobic center (hydrophic), hydrophobic aromatic ring (HA), and positive ion center (PI) pharmacodynamic feature elements were selected to generate 10 hydrogen pharmacophore models. Based on the highest correlation coefficient and fit value, lowest total cost and RMS value, Hypogen1 was selected for further analysis. The pharmacophore model Hypogen1 was validated using the test set (test set), Fisher (fisher randomisation) and bait set method (decoy set). The Hypogen1 pharmacophore can better predict the activity of the compounds in the test set, and the correlation coefficient between the predicted activity and the actual activity of the compounds is 0.847. The fisher method showed a statistical correlation between structure and activity within the 95% confidence interval. The bait set method showed a higher Enrichment factor (10.5), fitness (0.8022), indicating that Hypogen1 has a higher efficiency in distinguishing between active and inactive molecules.
Example 2: generation of Hiphop pharmacophore model
8 known BCR/ABL tyrosine kinase inhibitors were selected as the training set for the hipop pharmacophore model, hydrogen-bond acceptor (HBA), hydrogen-bond donor (HBD), hydrophobic center (hydrobic, H), aromatic Ring (RA), positively charged ion center (pos _ ionizable, PI), negatively charged ion center (NI) pharmacodynamic feature elements were selected to generate 10 hipop pharmacophore models. According to the score and the characteristic similarity, 10 pharmacophore models are clustered into two types, the pharmacophore with higher score of the two types is respectively selected to match with the active compound and the inactive compound in the training set, and the Hiphospho 1 model is found to be capable of better distinguishing the active compound from the inactive compound and is selected for further analysis. The pharmacophore model hipop 1 was validated using a test set. The method showed a higher Enrichment factor (10.95), a higher degree of fit (0.91), indicating that Hypogen1 has a higher efficiency in distinguishing between active and inactive molecules.
Example 3: the flow of virtual screening is as follows
The verified Hypogen1 and Hiphop1 pharmacophore models are respectively subjected to three-dimensional search in a ZINC Clean drug database, and through Linpinski' rule of five, ADMET and butt screening, the compounds obtained by screening the two ways are subjected to cytotoxicity experiments, the compounds with better activity are subjected to structure optimization, and the compounds with optimized structures are subjected to secondary screening. The general formula of the compound obtained by two screens has the following structural formula:
Figure BDA0002736543140000121
wherein:
(Ⅰ)R1hydrogen, methyl, ethyl, isopropyl,
R2Hydrogen, methyl, ethyl, isopropyl,
R3: by passing
Figure BDA0002736543140000122
And alkyl attached side chains.
Among the compounds screened after the structural optimization, ZINC21710815, ZINC36617889 and ZINC20617585 were purchased and subjected to cytotoxicity experiments. FIG. 4 shows the results of inhibition of K562, BaF3/WT and BaF3/T315I cells by three compounds tested in MTT and the toxic effect of compound ZINC21710815 on normal CCC-HEL-1 cells with IC50 values:
k562 cells
ZINC21710815(0.531μM/L)，ZINC36617889(35.878μM/L)，
ZINC20617585(62.813μM/L)。
BaF3/WT cells
ZINC21710815(0.512μM/L)，ZINC36617889(48.286μM/L)，
ZINC20617585(34.204μM/L)。
BaF3/T315I cell
ZINC21710815(0.88μM/L)，ZINC36617889(149.629μM/L)，
ZINC20617585(>300μM/L)。
CCC-HEL-1 cells
ZINC21710815(89.587μM/L)
The experimental results show that: ZINC21710815 has good inhibitory activity on K562 cells, BaF3/WT and BaF3/T315I cells but has no toxic inhibitory effect on normal human embryonic liver diploid cells, and ZINC21710815 is used as a representative compound to carry out cell cycle, apoptosis, autophagy and Western blot biological experiments for verification.
Example 4: effect of inhibiting cell cycle
K562 cells at 10X 10 per well5The density of individual cells was plated in triplicate in 6-well plates with BaF3/WT and BaF3/T315I cells at 5X 10 per well5Triplicate batches were plated in 6-well plates, the compound (ZINC21710815) was added to each well at a concentration of 0, 0.1, 1, 10 μ M/L for 24h, the cells were harvested, washed with PBS, 70% ethanol fixed cells at-20 ℃ overnight, and the fixative was washed away with PBS. Adding 100 mu LRNase A solution into the cell sediment to resuspend the cells, carrying out water bath at 37 ℃ for 30min, adding 400 mu L PI staining solution, mixing uniformly, incubating at 4 ℃ in the dark for 30min, and detecting by using a flow cytometer.
FIG. 5 shows that G for K562 cells with increasing concentration of the compounds of the invention2The cells in the stage are gradually increased, and the compound can induce K562 cell cycle to block at G2A period; for BaF3/WT and BaF3/T315I cells, G1The cells in the phase are gradually increased, and the compound can induce BaF3/WT and BaF3/T315I cell cycle block in G1And (4) period.
Example 5: effect of inhibiting apoptosis
K562, BaF3/WT and BaF3/T315I cells at 5X 10 per well5The density of each was plated in triplicate in 6-well plates, the compound was added to each well at a concentration of 0, 0.1, 1, 10. mu.M/L for 24h, the cells were harvested, washed with PBS, suspended in1 XBinding Buffer, centrifuged, the supernatant discarded, the cells resuspended in1 XBinding Buffer, and 100. mu.L of cells (1X 10) were added to each well (1X 10. mu.M/L)5Respectively), adding 5 mu L Annexin V-FITC, uniformly mixing at room temperature in the dark for 10min, adding 5 mu L PI, incubating in the dark for 5min, adding PBS to 500 mu L, and detecting by a flow cytometer after 1 h.
FIG. 6 shows that as the concentration of the compounds of the invention increases, the compounds induce apoptosis in K562, BaF3/WT and BaF3/T315I cells with increasing apoptotic cells in K562, BaF3/WT and BaF3/T315I cells.
Example 6: effect of Compounds on expression of apoptosis-related proteins, autophagy-related proteins, BCR/ABL and downstream proteins p-STAT5 and p-Crkl
Centrifuging at low temperature, collecting leukemia cells treated by compounds with different concentrations for 48h, and adding cell lysate for lysis. The lysate is centrifuged for 15min at 14000Xg in a low temperature centrifuge and the supernatant is ready for use. The absorbance at 570nm of the standards at different concentrations was measured and the absorbance values of blank wells were subtracted separately to plot a standard curve of absorbance at 570nm versus concentration (. mu.g/ml). The protein concentration of the sample to be tested is quantified using a standard curve. Adding 1 Xbuffer buffer solution into the protein sample solution to be detected, boiling for 10min, and subpackaging for later use.
Preparing separating gel and concentrated gel, inserting into comb, adding 1 × electrophoresis buffer solution, removing comb, and loading. The sample was first electrophoresed at a constant voltage of 80V until the dye approached the top of the gel and the band was flat, and then electrophoresed at a constant voltage of 120V until the dye approached the bottom of the gel. Then the gel is put in a 1 Xmembrane transferring buffer solution, and the membrane transferring operation is carried out according to the following sequence; white board (positive pole), fiber pad, filter paper, PVDF membrane, gel, filter paper, fiber pad and blackboard (negative pole), and the membrane is formed under the constant pressure of 100V and at the temperature of 4 ℃. The membrane was incubated in 5% skim milk at room temperature for 75min, the nonspecific binding on the membrane was blocked, and the blocked membrane was washed with TBST for 10min × 3 times. Adding primary antibody into the membrane, incubating overnight at 4 ℃, washing the membrane for 10min multiplied by 3 times by TBST, adding secondary antibody marked by HRP, incubating for 1h at room temperature, washing the membrane for 10min multiplied by 3 times by TBST, exposing, and analyzing the gray value of each specific strip by ImageJ software.
FIG. 6 shows that the expression level of apoptosis-related protein Cleaved Caspase3 is increased gradually with the increase of the concentration of the compound of the present invention, which may induce apoptosis of BaF3/WT and BaF3/T315I cells by apoptosis-related protein Caspase 3.
FIG. 7 shows that the expression level of autophagy-related proteins LC 3-II and Beclin1 is gradually increased with the increase of the concentration of the compound of the invention, which can induce the autophagy of BaF3/WT and BaF3/T315I cells through the autophagy-related proteins LC3 and Beclin 1.
FIG. 8 shows that the compound has an inhibition effect on the expression of BCR-ABL tyrosine kinase and downstream target proteins p-STAT5 and p-Crkl, and can inhibit the phosphorylation of BCR/ABL tyrosine kinase and downstream target proteins p-STAT5 and p-Crkl.
The compound of the invention is suitable for chronic granulocytic leukemia, and particularly the compound ZINC21710815 can strongly inhibit the proliferation of K562, BaF3/WT and BaF3/T315I cells, induce K562, BaF3/WT and BaF3/T315I cell cycle arrest, induce K562, BaF3/WT and BaF3/T315I apoptosis, inhibit the expression of BaF3/WT and BaF3/T315I apoptosis-related proteins and autophagy-related proteins, and inhibit the phosphorylation of BCR-ABL tyrosine kinase and downstream proteins thereof.

Claims (11)

1. A compound targeting BCR-ABL tyrosine kinase and represented by the general structural formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer and mixture form thereof, and a pharmaceutically acceptable salt thereof:
Figure FDA0002736543130000011
wherein: r1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isoPropyl;
R3: is selected from
Figure FDA0002736543130000012
Or an alkyl group.
2. A compound according to claim 1, wherein the substituent R3 of the compound of formula (i) is substituted to give the following formula:
Figure FDA0002736543130000013
wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl;
R4selected from methyl, hydrogen,
Figure FDA0002736543130000014
Figure FDA0002736543130000015
Wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl;
R5is selected from
Figure FDA0002736543130000016
Figure FDA0002736543130000017
Figure FDA0002736543130000021
Figure FDA0002736543130000022
Wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl; r6Is ethyl;
Figure FDA0002736543130000023
wherein R is1Selected from hydrogen, methyl, ethyl or isopropyl; r2Selected from hydrogen, methyl, ethyl or isopropyl; r7Selected from methyl or
Figure FDA0002736543130000024
3. A compound according to claim 2, or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein said compound of formula (ii) is selected from the group consisting of:
Figure FDA0002736543130000025
Figure FDA0002736543130000031
Figure FDA0002736543130000041
4. a compound according to claim 2, or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein said compound of formula (iii) is selected from:
Figure FDA0002736543130000042
Figure FDA0002736543130000051
Figure FDA0002736543130000061
Figure FDA0002736543130000071
Figure FDA0002736543130000081
5. a compound according to claim 2, or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein said compound of formula (iv) is selected from the group consisting of:
Figure FDA0002736543130000082
6. a compound according to claim 2, or tautomers, mesomers, racemates, enantiomers, diastereomers and mixtures thereof, and pharmaceutically acceptable salts thereof, wherein said compound of formula (v) is selected from the group consisting of:
Figure FDA0002736543130000091
7. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
8. Use of a compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, for inhibiting BCR/ABL tyrosine kinase.
9. Use of a compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, for antagonizing the T315I mutation.
10. Use of a compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of leukemia.
11. The use according to claim 10, wherein the leukemia is chronic myeloid leukemia.
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