CN112538063A - MCL-1 inhibitor and preparation method and application thereof - Google Patents
MCL-1 inhibitor and preparation method and application thereof Download PDFInfo
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- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 title claims abstract description 56
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention discloses an MCL-1 inhibitor, a preparation method and application thereof. According to the invention, oxalic acid ethylene diester and a compound A containing naphthylethanone react for 4-6 hours to obtain a compound B, then the compound B reacts with a compound C containing 3-hydroxyisobenzofuran-1 (3H) -ketone to obtain a compound D, the compound D is dissolved in 10-15 mL of a 40% sodium hydroxide aqueous solution to react, and after pH adjustment, extraction, evaporation and recrystallization, a compound E is obtained, and the compound E reacts with 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, 1-hydroxybenzotriazole and halogen substituent-containing o-toluidine, and after the reaction, the compound E is washed and subjected to solid recrystallization to obtain the MCL-1 inhibitor. The MCL-1 inhibitor can be used as a tumor treatment drug or can be used together with a BCL-2 inhibitor, namely, vitamin E Toxol, so that the effect of serving as a sensitizer of the BCL-2 inhibitor can be achieved, and the effect of serving as a reversal agent of drug resistance of a receiving drug body to the vitamin E Toxol can be achieved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an MCL-1 inhibitor, and a preparation method and application thereof.
Background
Apoptosis (apoptosis), also known as programmed cell death (programmed cell death), is a self-ordered death mode of cells regulated by genes and has important functions on the development of organisms and the maintenance of cell morphology. The maladjustment of the apoptosis pathway not only directly participates in the generation and growth of tumors, but also participates in the formation of drug resistance of the tumors, so that the tumors resist the killing of drugs. Therefore, induction of apoptosis has become an important strategy for tumor therapy and drug development. The opening and closing of apoptosis is mainly controlled by BCL-2 family proteins, which are mainly divided into two classes: one class is anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL; another class is the pro-apoptotic proteins, including Bax, Bak, Bim, Noxa, and Puma, among others. The apoptosis-promoting protein forms oligomerization (oligomerization) on the outer membrane of mitochondria, promotes the opening of the outer membrane pore canal of mitochondria, causes cytochrome C to be released from mitochondria to cytoplasm, further stimulates Caspase cascade reaction, and finally leads to apoptosis. The anti-apoptosis proteins BCL-2, MCL-1 and BCL-xL inhibit the formation of Bax and Bak oligomerization through interaction with pro-apoptosis proteins, thereby inhibiting apoptosis.
The activation of tumor cell apoptosis has always been an important strategy for tumor drug development. The BCL-2 inhibitor venetocix (venetocalax), developed in combination by Abb Vie Inc (Abb Vie Inc) and switzerland Roche (Roche), was approved by the FDA for leukemia therapy in 2016, now became a first-line drug for chronic myeloid leukemia, widely used for clinical therapy, and many companies have conducted clinical trials of efficacy for solid tumors. However, studies demonstrated that Venetock is capable of specifically inhibiting BCL-2 and BCL-xL, but not MCL-1, with binding dissociation constants (Kd) of 0.010nM, 48nM and >444nM for BCL-2, BCL-xL and MCL-1, respectively. Thus, MCL-1 retains its anti-apoptotic function during ABT-199 treatment, conferring tumor cell tolerance to Venetork. MCL-1 is not only an important target for targeting apoptosis, but also a key molecule for drug resistance in clinical treatment of BCL-2 inhibitors.
However, specific and effective MCL-1 inhibitors are still lacking in clinic, so that the development of the MCL-1 inhibitors becomes a research hotspot for the development of tumor drugs. Although several research papers have reported the development of MCL-1 small molecule inhibitors in recent years, these small molecule drugs are currently in preclinical or clinical research stage, and their toxicity and effectiveness need to be further evaluated clinically. Since no specific and effective MCL-1 inhibitor is approved for clinical tumor treatment at present, the development of specific and highly effective MCL-1 inhibitors is still an urgent necessity on a global scale.
Disclosure of Invention
The invention aims at providing an MCL-1 inhibitor.
It is still another object of the present invention to provide a process for preparing the above MCL-1 inhibitor.
Another object of the present invention is to provide the use of the above MCL-1 inhibitor.
The invention is realized by an MCL-1 inhibitor, which has a chemical structural formula shown as the following formula (I):
in the formula (I), R1Is selected from
And
any one of the above;
R2any one selected from C, N;
R3any one selected from O, NH;
r4 is selected from any one of F, Cl, Br and I.
Preferably, said R is1Is composed of
The R is2Is C, R3Is O, R4Is Cl, and the chemical structural formula of the inhibitor is as follows:
the invention further discloses a preparation method of the MCL-1 inhibitor, which comprises the following steps:
(1) dissolving 0.8-1.2 mmol of ethylene oxalate and 0.8-1.2 mmol of compound A in 20-30 mL of toluene solution, slowly adding 4-6 mmol of sodium hydride, stirring at 0 ℃, heating to 80-100 ℃, reacting for 4-6 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain compound B; wherein the compound A is at least one of acetophenone, 1- (isoquinoline-6-yl) ethanone, 1- (1H-indazol-6-yl) ethanone, 1- (1H-indol-6-yl) ethanone, 1- (1H-benzotriazol-6-yl) ethanone and 1- (quinazoline-7-yl) ethanone;
(2) dissolving 0.8-1.2 mmol of compound B and 0.8-1.2 mmol of compound C in 10-20 mL of ethanol solution, adding 1.5-2.5 mmol of cesium carbonate, heating and refluxing for 5-6 hours, evaporating the solvent, washing the obtained solid with ethanol, and drying to obtain a compound D; wherein the compound C is 3-hydroxyisobenzofuran-1 (3H) -ketone or 3-hydroxyisoindol-1-ketone; at least one of 7-hydroxy-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one and 7-hydroxyfuro [3,4-b ] pyridin-5 (7H) -one;
(3) dissolving 0.8-1.2 mmol of the compound D in 10-15 mL of 40% sodium hydroxide aqueous solution, stirring and reacting at 50-70 ℃ for about 2-4 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding 1N hydrochloric acid solution, adjusting the pH value to 5-6, extracting with dichloromethane, evaporating to dryness, and recrystallizing the residue with methanol to obtain a compound E;
(4) dissolving 0.8-1.2 mmol of the compound E, 1.0-1.2 mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and 1.0-1.2 mmol of 1-hydroxybenzotriazole in 20-25 mL of dichloromethane, stirring for 30-60 minutes, adding 1.1-1.3 mmol of o-toluidine containing halogen substituent, heating and refluxing for about 5-7 hours, tracking reaction by TLC, washing with water after the reaction is finished, separating out solid, and recrystallizing with methanol to obtain a compound F, namely an MCL-1 inhibitor; wherein the halogen in the o-toluidine is at least one of F, Cl, Br and I.
Preferably, in step (1), the compound a is an acetophenone;
preferably, in step (2), the compound C is 3-hydroxyisobenzofuran-1 (3H) -one;
preferably, in step (4), the halogen in the o-toluidine is Cl.
The invention further discloses application of the MCL-1 inhibitor in preparing a medicament for inducing apoptosis of tumor cells.
The invention further discloses application of the MCL-1 inhibitor and the BCL-2 inhibitor in combination as a tumor treatment drug.
The invention overcomes the defects of the prior art and provides an MCL-1 inhibitor, a preparation method and application thereof. The preparation of the MCL-1 inhibitor comprises four steps which are respectively as follows:
(1) dissolving oxalic acid ethylene ester (1mmol) and a compound A (1mmol) in 20-30 mL of toluene solution, slowly adding sodium hydride (5mmol), stirring at 0 ℃, heating to 80-100 ℃, reacting for 4-6 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain a compound B:
wherein R is1Is selected from
(2) Dissolving a compound B (1mmol) and a compound C (1mmol) in 10-20 mL of ethanol solution, adding cesium carbonate (2mmol), heating and refluxing for 5-6 hours, evaporating the solvent, washing the obtained solid with ethanol, and drying to obtain a compound D:
wherein R is2Selected from C, N; r3Selected from O, NH;
(3) dissolving a compound D (1mmol) in 10-15 mL of a 40% sodium hydroxide aqueous solution, stirring and reacting at 50-70 ℃ for about 2-4 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding a 1N hydrochloric acid solution, adjusting the pH value to be 5-6, extracting with dichloromethane, evaporating to dryness, and recrystallizing the residue with methanol to obtain a compound E:
(4) dissolving a compound E (1mmol) and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (1.1mmol) and 1-hydroxybenzotriazole (1.1mmol) in 20-25 mL of dichloromethane, stirring for 30-60 minutes, adding 1.2mmol of halogen substituent-containing o-toluidine, heating and refluxing for about 5-7 hours, tracking the reaction by TLC, washing with water after the reaction is finished, separating out a solid, and recrystallizing with methanol to obtain a compound F, namely the MCL-1 inhibitor:
wherein R is4Is selected from any one of F, Cl, Br and I.
The obtained MCL-1 inhibitor targets an MCL-1BH3 binding pocket, a lead compound MI-238 of the MCL-1 inhibitor is obtained by screening from a small molecule database through a polarized Fluorescence technology (Fluorescence Polarization), and the MI-238 can induce MCL-1-dependent apoptosis and has a remarkable anti-tumor synergistic effect with a BCL-2 inhibitor Venetork on various tumor cells.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) the MCL-1 inhibitor can be used as a medicine for inducing tumor apoptosis, can be applied to tumor treatment, and is suitable for and not limited to multiple myeloma and leukemia including chronic myelogenous leukemia, acute myelogenous leukemia, chronic granulocytic leukemia and the like;
(2) the MCL-1 inhibitor can be combined with a BCL-2 inhibitor, namely vernetoclax (venenooctax), to be used as an application of a tumor treatment drug, and in the combined drug, the MCL-1 inhibitor can have the efficacy of serving as a sensitizer of the BCL-2 inhibitor and can also have the efficacy of serving as a reversal agent of drug resistance of a receptor body to the vernetoclax.
Drawings
FIG. 1 is a schematic representation of the binding position of Mcl-1 inhibitor MI-238 to Mcl-1 protein;
FIG. 2 is the binding constant of Mcl-1 inhibitor MI-238 to Mcl-1 protein;
FIG. 3 is a graph showing that MI-238 specifically induces MCL-1 dependent apoptosis in examples of the present invention;
FIG. 4 shows the effect of MI-238 sensitizing BCL-2 inhibitor Venetoposide (venetocalax) in the present example FIG. 1;
FIG. 5 is a graph of the effect of MI-238-sensitized BCL-2 inhibitor Venetoposide (venetocalax) in an example of the present invention, FIG. 2.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
(1) Dissolving 0.8mmol of ethylene oxalate and 1.2mmol of acetophenone (compound A) in 30mL of toluene solution, slowly adding 6mmol of sodium hydride, stirring at 0 ℃, heating to 100 ℃, reacting for 6 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain a compound B;
(2) dissolving 1.2mmol of compound B and 0.8mmol of 3-hydroxyisobenzofuran-1-one (compound C) in 10mL of ethanol solution, adding 1.5mmol of cesium carbonate, heating and refluxing for 5 hours, evaporating the solvent to dryness, washing the obtained solid with ethanol, and drying to obtain a compound D;
(3) dissolving 0.8mmol of the compound D in 15mL of 40% sodium hydroxide aqueous solution, stirring and reacting at 70 ℃ for about 4 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding 1N hydrochloric acid solution, adjusting the pH value to 6, extracting by using dichloromethane, evaporating to dryness, and recrystallizing the residue by using methanol to obtain a compound E;
(4) dissolving 1.2mmol of the compound E, 1.0mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and 1.0mmol of 1-hydroxybenzotriazole in 20mL of dichloromethane, stirring for 30 minutes, adding 1.1mmol of 4-chloro-2-methylaniline (o-toluidine containing halogen substituent), heating and refluxing for about 5 hours, tracking the reaction by TLC, washing with water after the reaction is finished, separating out a solid, and recrystallizing with methanol to obtain a compound F, namely the MCL-1 inhibitor 1.
Example 2
(1) Dissolving 1.2mmol of ethylene oxalate and 0.8mmol of acetophenone (compound A) in 20mL of toluene solution, slowly adding 4mmol of sodium hydride, stirring at 0 ℃, heating to 80 ℃, reacting for 4 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain a compound B;
(2) dissolving 0.8mmol of the compound B and 1.2mmol of 3-hydroxyisobenzofuran-1-one (compound C) in 20mL of ethanol solution, adding 2.5mmol of cesium carbonate, heating and refluxing for 6 hours, evaporating the solvent, washing the obtained solid with ethanol, and drying to obtain a compound D;
(3) dissolving 1.2mmol of the compound D in 10mL of 40% sodium hydroxide aqueous solution, stirring and reacting at 50 ℃ for about 2 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding 1N hydrochloric acid solution, adjusting the pH value to be 5, extracting by using dichloromethane, evaporating to dryness, and recrystallizing the residue by using methanol to obtain a compound E;
(4) dissolving 0.8mmol of the compound E, 1.2mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and 1.2mmol of 1-hydroxybenzotriazole in 25mL of dichloromethane, stirring for 60 minutes, adding 1.3mmol of 4-chloro-2-methylaniline (o-toluidine containing halogen substituent), heating and refluxing for about 7 hours, tracking the reaction by TLC, washing with water after the reaction is finished, separating out a solid, and recrystallizing with methanol to obtain a compound F, namely the MCL-1 inhibitor 2.
Example 3
(1) Dissolving 1.0mmol of ethylene oxalate and 1.0mmol of acetophenone (compound A) in 25mL of toluene solution, slowly adding 5mmol of sodium hydride, stirring at 0 ℃, heating to 90 ℃, reacting for 5 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain a compound B;
(2) dissolving 1.0mmol of compound B and 1.0mmol of 3-hydroxyisobenzofuran-1-one (compound C) in 15mL of ethanol solution, adding 2.0mmol of cesium carbonate, heating and refluxing for 5.5 hours, evaporating the solvent to dryness, washing the obtained solid with ethanol, and drying to obtain a compound D;
(3) dissolving 1.0mmol of the compound D in 12mL of 40% sodium hydroxide aqueous solution, stirring and reacting at 60 ℃ for about 3 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding 1N hydrochloric acid solution, adjusting the pH value to 6, extracting by using dichloromethane, evaporating to dryness, and recrystallizing the residue by using methanol to obtain a compound E;
(4) dissolving 1.0mmol of the compound E, 1.1mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and 1.1mmol of 1-hydroxybenzotriazole in 22mL of dichloromethane, stirring for 40 minutes, adding 1.2mmol of 4-chloro-2-methylaniline (o-toluidine containing halogen substituent), heating and refluxing for about 6 hours, tracking the reaction by TLC, washing with water after the reaction is finished, separating out a solid, and recrystallizing with methanol to obtain a compound F, namely the MCL-1 inhibitor 3.
Examples 4 to 8
Examples 4-8 are substantially similar to example 3 above, with the differences shown in Table 1 below:
TABLE 1 comparison of the differences between examples 4-8 and example 3
Effect example 1
Through molecular docking and virtual screening by using an MCL-1BH3 binding pocket, the binding positions of the small molecule MI-238 and the Mcl-1 inhibitor MI-238 and the Mcl-1 protein are obtained, and as shown in figure 1, the MI-238 is combined with arginine at position 263 and methionine at position 250 of an MCL-1BH3 domain.
A sample of recombinant human MCL-1 protein (100. mu.g) was placed in a titration needle of an isothermal titration calorimeter iTC200, and buffer was placed in the sample cell at a temperature set at 25 ℃.16 titrations were performed with titration parameters set at 5 μ Cal/sec. The results of the isothermal titration experiment (ITC) are shown in FIG. 2, and it can be seen from FIG. 2 that MI-238 binds to MCL-1 at a binding constant of 0.15. mu.M.
Effect example 2
The Parental (Parental) and MCL-1 knock-out (MCL-1KO) non-small cell lung cancer cell line H1299, and wild-type (WT) and MCL-1 knock-out (MCL-1KO) Mouse Embryonic Fibroblasts (MEFs) were treated with 20. mu.M MI-238 for 48 hours, and then the number of apoptotic cells was determined using Annexin V. As shown in fig. 3, the results indicate that MI-238 was able to significantly induce apoptosis in the parental or wild-type cells, but not in the MCL-1 knockout cells. This result confirmed that: MI-238 was able to specifically induce MCL-1 dependent apoptosis.
Effect example 3
The non-small cell lung cancer cell line H1299 was treated with 1. mu.M of Venetocker (Venetochlax), 5. mu.M of MI-238 and their combination for 48 hours, respectively, and then the number of apoptotic cells was measured by Annexin V, as shown in FIGS. 4 and 5. As can be seen from fig. 4 and 5, venetocks induced 3.07% of tumor cell apoptosis alone, MI-238 induced 6.16% of tumor cell apoptosis alone, and the combination of venetocks and MI-238 induced 24% of tumor cell apoptosis. The conclusion proves that: MI-238 and Vernetitol have obvious synergistic antitumor effect.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (6)
1. An MCL-1 inhibitor, wherein the inhibitor has the formula (i):
in the formula (I), R1Is selected from
And
any one of the above;
R2any one selected from C, N;
R3any one selected from O, NH;
r4 is selected from any one of F, Cl, Br and I.
2. The MCL-1 inhibitor of claim 1 wherein the inhibitor has the chemical formula:
3. a process for the preparation of an MCL-1 inhibitor as claimed in claim 1 or 2, characterized in that the process comprises the steps of:
(1) dissolving 0.8-1.2 mmol of ethylene oxalate and 0.8-1.2 mmol of compound A in 20-30 mL of toluene solution, slowly adding 4-6 mmol of sodium hydride, stirring at 0 ℃, heating to 80-100 ℃, reacting for 4-6 hours, evaporating the solvent, and recrystallizing the residue with methanol to obtain compound B; wherein the compound A is at least one of acetophenone, 1- (isoquinoline-6-yl) ethanone, 1- (1H-indazol-6-yl) ethanone, 1- (1H-indol-6-yl) ethanone, 1- (1H-benzotriazol-6-yl) ethanone and 1- (quinazoline-7-yl) ethanone;
(2) dissolving 0.8-1.2 mmol of compound B and 0.8-1.2 mmol of compound C in 10-20 mL of ethanol solution, adding 1.5-2.5 mmol of cesium carbonate, heating and refluxing for 5-6 hours, evaporating the solvent, washing the obtained solid with ethanol, and drying to obtain a compound D; wherein the compound C is 3-hydroxyisobenzofuran-1 (3H) -ketone or 3-hydroxyisoindol-1-ketone; at least one of 7-hydroxy-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one and 7-hydroxyfuro [3,4-b ] pyridin-5 (7H) -one;
(3) dissolving 0.8-1.2 mmol of the compound D in 10-15 mL of 40% sodium hydroxide aqueous solution, stirring and reacting at 50-70 ℃ for about 2-4 hours, tracking the reaction by TLC, stopping heating after the reaction is finished, dropwise adding 1N hydrochloric acid solution, adjusting the pH value to 5-6, extracting with dichloromethane, evaporating to dryness, and recrystallizing the residue with methanol to obtain a compound E;
(4) dissolving 0.8-1.2 mmol of the compound E, 1.0-1.2 mmol of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide and 1.0-1.2 mmol of 1-hydroxybenzotriazole in 20-25 mL of dichloromethane, stirring for 30-60 minutes, adding 1.1-1.3 mmol of o-toluidine containing halogen substituent, heating and refluxing for about 5-7 hours, tracking reaction by TLC, washing with water after the reaction is finished, separating out solid, and recrystallizing with methanol to obtain a compound F, namely an MCL-1 inhibitor; wherein the halogen in the o-toluidine is at least one of F, Cl, Br and I.
4. The method of preparing an MCL-1 inhibitor as in claim 3 wherein in step (1) compound a is an acetophenone;
in step (2), the compound C is 3-hydroxyisobenzofuran-1 (3H) -one;
in the step (3), the halogen in the o-toluidine is Cl.
5. Use of an MCL-1 inhibitor as claimed in claim 1 or 2 as a medicament for inducing apoptosis in tumor cells.
6. Use of an MCL-1 inhibitor as defined in claim 1 or 2 in combination with a BCL-2 inhibitor as a medicament for the treatment of tumors.
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| JP2019034941A (en) * | 2017-08-21 | 2019-03-07 | 日産化学株式会社 | Oxime compound and herbicide |
| US20200316011A1 (en) * | 2017-10-26 | 2020-10-08 | Emory University | Targeting Mcl-1 to Enhance DNA Replication Stress Sensitivity for Cancer Therapy |
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| JP2019034941A (en) * | 2017-08-21 | 2019-03-07 | 日産化学株式会社 | Oxime compound and herbicide |
| US20200316011A1 (en) * | 2017-10-26 | 2020-10-08 | Emory University | Targeting Mcl-1 to Enhance DNA Replication Stress Sensitivity for Cancer Therapy |
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