CN117886817A - CDK6/BRD4 bispecific inhibitor and preparation method and application thereof - Google Patents
CDK6/BRD4 bispecific inhibitor and preparation method and application thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a CDK6/BRD4 double-target inhibitor, which is selected from compounds with a structure shown as a formula I or pharmaceutically acceptable salts thereof, wherein L is selected from-HN- (CH) 2 ) m ‑NH‑、 m is an integer of 1 to 6, n is an integer of 0 to 6, o is an integer of 0 to 6, p is an integer of 0 to 6, and q is an integer of 0 to 6. The CDK6/BRD4 double-target inhibitor has better effect on human breast cancer cells and has fine effect on normal human breast epitheliumLess cytotoxic and maintains good in vitro enzyme inhibition activity against CDK6 and BRD 4. The invention discloses application of a CDK6/BRD4 double-target inhibitor in preparation of a medicament for treating CDK6/BRD4 mediated diseases. The invention discloses application of a CDK6/BRD4 double-target inhibitor in preparation of a medicament for treating or preventing triple negative breast cancer.
Description
Technical Field
The invention belongs to the field of small molecule compounds, and relates to a CDK6/BRD4 bispecific inhibitor, and a preparation method and application thereof.
Background
Breast cancer is one of the most common malignant tumors in women, and although mortality rate is remarkably reduced in recent years, incidence rate is increased year by year, accounting for 30% of all newly diagnosed cancers of women, and is already more than lung cancer, and becomes the first cancer worldwide. Triple Negative Breast Cancer (TNBC) is known as "advanced disease of breast cancer", accounting for about 10-20% of all breast cancers. TNBC is characterized by the lack of estrogen receptor (er), progestogen receptor (pr) and human EGF receptor-2 (HER-2), the most powerful of breast cancer diseases. To date, there is no effective treatment for TNBC, and most patients can only receive chemotherapy. However, the extensive adverse reactions associated with chemotherapy make patients susceptible to drug resistance, leading to poor prognosis, high recurrence and metastasis rates. The development of targeted drugs and precision therapies benefits most cancer patients. The development of drugs effective in the treatment of TNBC not only has less harm to the body of the patient, but also can realize complete cure.
It has been demonstrated that combining key pharmacophores of two or more drugs into a single multifunctional molecule, a design strategy that regulates multiple cellular pathways is effective. The CDK4/6 inhibitor, palbociclib, was reported to have a strong synergistic effect with the BET inhibitor JQ-1 on TNBC giant, further revealing the mechanism of resistance to combination therapy.
It is therefore a significant effort to design inhibitors with dual targeting functions.
Disclosure of Invention
The invention aims to provide a CDK6/BRD4 double-target inhibitor.
Another object of the invention is to provide a method for preparing the CDK6/BRD4 dual-target inhibitor.
It is a further object of the invention to provide the use of said CDK6/BRD4 dual-target inhibitor.
The aim of the invention is achieved by the following technical scheme:
a CDK6/BRD4 dual-target inhibitor selected from compounds having the structure shown in formula I:
wherein L is selected from-HN- (CH) 2 ) m -NH- m is an integer of 1 to 6, n is an integer of 0 to 6, o is an integer of 0 to 6, p is an integer of 0 to 6, and q is an integer of 0 to 6.
Preferably, L is selected from the group consisting of-HN- (CH) 2 ) m -NH- m is an integer of 2 to 6, n is 0, p is 1, and q is 1.
More preferably, L is selected fromn is 0 and p is 1.
As a preferred embodiment of the invention, the CDK6/BRD4 dual-target inhibitor is selected from compounds having the structure shown in formula II:
wherein m is as previously described.
As a preferred embodiment of the invention, the CDK6/BRD4 dual-target inhibitor is selected from compounds having the structure shown in formula III:
wherein n is as previously described.
As a preferred embodiment of the invention, the CDK6/BRD4 dual-target inhibitor is selected from compounds having the structure shown in formula IV:
further, the CDK6/BRD4 dual-target inhibitor is a compound with the structure shown as the following or pharmaceutically acceptable salt thereof:
the invention also aims to provide a preparation method of the CDK6/BRD4 double-target inhibitor, which comprises the following synthetic route:
wherein L is selected fromAs described in detail above.
The method comprises the following steps:
step (a), using isopropylAlcohol (i-PrOH) as reaction solvent, DIPEA as acid-binding agent, in N 2 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one (Compound 1) and under protectionReflux reaction to obtain intermediate 2;
step (b) in trifluoroacetic acid (CF) with Dichloromethane (DCM) as the reaction solvent 3 COOH) in the presence of a protecting group, removing the protecting group of the intermediate 2 at room temperature to obtain an intermediate 3;
step (c), using DCM as a reaction solvent, mixing the intermediate 3 with p-carboxybenzaldehyde and HATU, and reacting at room temperature by using DIPEA as an acid-binding agent to obtain an intermediate 4;
step (d) using N, N-Dimethylacetamide (DMAC) as a reaction solvent, intermediate 4, compound 5 and PTSA, naHSO 3 Adding the mixture into a reaction solvent, and carrying out reflux reaction at 120 for 4-8 hours to obtain the target compound with the structure shown in the formula I.
In step (a), the 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one andthe molar ratio of (2) is 1:1.5-1:2; the molar ratio of the 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one to the DIPEA is 1:3-1:4.
In step (b), the molar ratio of intermediate 2 to trifluoroacetic acid is 1:4 to 1:7.
In the step (c), the molar ratio of the intermediate 3 to the p-carboxybenzaldehyde is 1:1.25-1:2; the mol ratio of the intermediate 3 to the HATU is 1:2-1:2.5; the molar ratio of the intermediate 3 to the DIPEA is 1:7-1:15.
In the step (d), the molar ratio of the intermediate 4 to the compound 5 is 1:1-1:3; the mol ratio of the intermediate 4 to the PTSA is 1:0.1-1:0.3; intermediate 4 and NaHSO 3 The molar ratio of (2) is 1:1.5-1:3.
Another object of the invention is to provide the use of said CDK6/BRD4 dual-target inhibitor in the preparation of a medicament for the treatment of CDK6/BRD4 mediated disorders.
The invention also provides an application of the CDK6/BRD4 double-target inhibitor in preparing a medicine for treating or preventing triple negative breast cancer.
Another object of the invention is to provide a pharmaceutical composition comprising said CDK6/BRD4 dual-target inhibitor and a pharmaceutically acceptable carrier.
Preferably, the dosage form of the pharmaceutical composition is any one of tablets, capsules, powder, syrup, solution, suspending agent and freeze-dried powder injection.
The invention has the beneficial effects that:
the CDK6/BRD4 double-target inhibitor has good inhibition effect on human breast cancer cells MDA-MB-231 and BT549, has low toxicity on human normal breast epithelial cells MCF-10A, and maintains good in-vitro enzyme inhibition activity on CDK6 and BRD 4. In vivo xenograft mouse tumor models show that the compounds have excellent anti-tumor activity. Therefore, the CDK6/BRD4 double-target inhibitor has great potential as an anti-tumor drug.
The CDK6/BRD4 double-target inhibitor can be used as a single therapeutic agent of tumors or can be combined with other antitumor drugs, so that the effects of improving the curative effect of the existing antitumor drugs and reducing the dosage and toxicity are achieved.
Drawings
Fig. 1 shows the trend of tumor volume change during treatment.
Figure 2 is tumor weight at day 21 post-treatment.
Figure 3 shows the change in body weight of mice during treatment.
FIG. 4 is HE staining of major organs such as heart, liver, spleen, lung and kidney; scale, 50 m.
Detailed Description
The technical scheme of the invention is further described by the following specific examples.
Example 1
Wherein L is selected from
Step (a), treatment with 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one (Compound 1, 200mg,0.76 mmol) and formulaThe compound shown (1.4 mmol) was used as starting material in 20mL isopropanol as solvent and DIPEA (0.45 mL,2.96 mmol) as acid-binding agent in N 2 Reflux reaction for 2 hours under protection, spin-drying the reaction mixture, and separating by silica gel column chromatography (DCM/meoh=50/1, V/V) to give white powder intermediate 2;
step (b), intermediate 2 (0.54 mmol) was dissolved in 10mL dichloromethane and CF was added 3 COOH (0.4 mL,3.5 mmol), at room temperature for 6 hours, concentrated under reduced pressure to give intermediate 3;
step (c), intermediate 3 (0.52 mmol) was mixed with p-carboxybenzaldehyde (100 mg,0.66 mmol), HATU (360 mg,0.94 mmol), DIPEA (0.8 ml,7.01 mmol) and reacted at room temperature for 2 hours, isolated by silica gel column chromatography (DCM/meoh=35/1) to give intermediate 4;
step (d), intermediate 4 (0.47 mmol) and Compound 5 (0.61 mmol) were dissolved in 12mL of N, N-Dimethylacetamide (DMAC), and PTSA (20 mg,0.11 mmol) and NaHSO were added 3 (110 mg,1.05 mmol) was refluxed at 120for 4-8 hours and column chromatography on silica gel (DCM/MeOH=25/1, V/V) to give the desired product.
TABLE 1 Compounds synthesized according to the invention
Compound BC1: n- (2- ((8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyridine [2, 3-d)]Pyrimidin-2-yl) amino) ethyl) -4- (5, 7-dimethoxy-4-oxy)Substituted-3, 4-dihydroquinazolin-2-yl) benzamides. Yield 44%; 1 H NMR(500MHz,DMSO-d 6 )12.12(s,1H),8.79-8.57(m,2H),8.25(d,J8.1Hz,2H),7.97(d,J8.1Hz,2H),6.79(d,J2.3Hz,1H),6.57(d,J2.5Hz,1H),6.09(s,1H),5.86(s,1H),3.91(s,3H),3.87(s,2H),3.56(s,4H),2.32(s,3H),1.95(s,2H),1.69(d,J52.9Hz,3H). 13 C NMR(151MHz,DMSO-d 6 )166.15,164.79,163.10,161.59,161.44,160.21,157.32,156.11,153.27,152.68,145.97,137.23,135.01,128.02,127.87,116.35,105.32,101.87,98.47,98.22,56.49,56.15,52.53,41.17,40.51,28.00,25.64,17.16.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 618.2435found618.2434; purity 98.12% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 3.350min).
Compound BC2: n- (4- ((8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyridine [2, 3-d)]Pyrimidin-2-yl) amino) butyl) -4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) benzamide. Yield 65%; 1 H NMR(600MHz,DMSO-d 6 )12.14(s,1H),8.64(t,J5.7Hz,1H),8.24(d,J8.1Hz,2H),7.96(d,J8.0Hz,2H),7.83(d,J6.1Hz,1H),7.62(s,1H),6.79(d,J2.3Hz,1H),6.57(d,J2.4Hz,1H),6.06(s,1H),3.91(s,3H),3.87(s,3H),3.42-3.36(m,3H),3.33-3.26(m,2H),2.31(s,3H),2.18(t,J7.4Hz,1H),1.95(d,J36.7Hz,3H),1.74-1.67(m,2H),1.62(s,6H). 13 C NMR(151MHz,DMSO-d 6 )165.76,164.80,163.15,161.58,161.45,160.17,157.35,156.09,153.31,152.66,137.34,134.93,128.01,127.75,115.96,105.47,101.89,98.48,56.48,56.15,52.45,41.13,31.76,29.49,27.89,25.49,22.56,17.15.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 646.2748found646.2750; purity 97.83% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm) MeOH/H 2 O85/15R t 4.245min).
Compound BC3: cyclopentyl-2- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) benzoyl) piperazin-1-yl) amino) -5-methylpyridine [2,3-d]Pyrimidin-7 (8H) -ones. Yield 42%; 1 H NMR(600MHz,DMSO-d 6 )12.17(s,1H),8.75(s,1H),8.26(d,J8.4Hz,1H),7.61(d,J8.3Hz,2H),6.78(d,J2.3Hz,2H),6.58(d,J2.3Hz,1H),6.15(d,J1.4Hz,1H),5.85-5.73(m,1H),3.91(s,1H),3.87(s,3H),3.78(s,3H),3.48(s,1H),2.34(d,J1.2Hz,3H),2.24(d,J10.7Hz,2H),1.92(s,2H),1.74(s,2H),1.61(s,2H). 13 C NMR(151MHz,DMSO-d 6 )169.03,164.80,163.06,161.48,160.24,157.16,156.00,153.33,152.73,145.83,138.89,133.77,128.32,127.68,117.33,106.13,105.35,101.89,98.41,56.50,56.14,52.69,29.47,27.95,25.61,22.56,17.14.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 659.2701found 659.2732; purity 97.69% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm) MeOH/H 2 O85/15R t 4.471min).
Compound BC4: 8-cyclopentyl-2- (4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) benzoyl) piperazin-1-yl) -5-methylpyridine [2,3-d]Pyrimidin-7 (8H) -ones. Yield 37%; 1 H NMR(500MHz,DMSO-d 6 )12.15(s,1H),8.76(s,1H),8.31-8.10(m,3H),7.66-7.50(m,2H),6.79(s,1H),6.59(s,1H),6.16(s,1H),4.03-3.87(m,5H),3.56(d,J69.6Hz,3H),3.16(s,2H),2.35(s,3H),2.31-1.53(m,11H). 13 C NMR(126MHz,DMSO-d 6 )169.06,164.82,163.08,161.64,160.25,157.13,156.02,153.31,152.97,150.23,145.82,138.77,133.80,128.33,127.68,117.34,106.16,105.23,101.93,98.42,63.59,56.51,56.14,52.73,29.25,27.95,25.60,17.12.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 644.2592found 644.2592; purity 98.32% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 4.134min).
Compound BC5: 8-cyclopentyl-2- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) benzoyl) azetidin-3-yl) methyl) amino) -5-methylpyridine [2,3-d ]]Pyrimidin-7 (8H) -ones. Yield 54%; 1 H NMR(600MHz,DMSO-d 6 )12.18(s,1H),8.71(s,1H),8.45(s,1H),8.24(d,J7.9Hz,2H),7.79(d,J8.0Hz,2H),6.78(s,1H),6.57(s,1H),6.13(s,1H),4.70-4.61(m,2H),4.42(s,2H),4.13(s,1H),3.89(d,J22.7Hz,6H),2.34(s,3H),2.22(s,2H),1.96(d,J39.5Hz,3H),1.73(s,2H),1.58(s,2H). 13 C NMR(151MHz,DMSO-d 6 )164.80,162.96,161.47,160.16,153.28,152.69,145.96,134.94,128.29,106.34,105.36,101.90,98.48,56.49,56.15,40.52,29.48,28.08,25.57,17.16.HRMS(ESI):[M+H] + calcd for C 27 H 30 NO 4 622.2772found 622.2722; purity 97.81% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 3.481min).
Compound BC6: 8-cyclopentyl-2- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) benzoyl) pyrrolidin-3-yl) methyl) amino) -5-methylpyridine [2,3-d]Pyrimidin-7 (8H) -ones. Yield 38%; 1 H NMR(600MHz,DMSO-d 6 )12.14(d,J10.3Hz,1H),8.62(d,J37.6Hz,1H),8.20(dd,J15.9,8.0Hz,2H),8.06-7.82(m,1H),7.62(dd,J36.6,8.0Hz,2H),6.77(d,J2.4Hz,1H),6.55(dd,J15.9,2.4Hz,1H),6.07(dd,J19.1,10.8Hz,1H),3.88(d,J22.7Hz,6H),3.82(s,1H),3.65(dt,J15.9,8.1Hz,1H),3.58-3.44(m,3H),3.27(d,J6.8Hz,1H),3.11(d,J7.6Hz,1H),2.31(d,J18.7Hz,3H),2.21-2.12(m,2H),2.07-1.86(m,3H),1.79-1.53(m,6H). 13 C NMR(151MHz,DMSO-d 6 )168.01,164.78,164.48,161.61,161.46,160.21,153.51,153.32,146.63,140.06,133.83,133.73,128.07,128.01,127.67,105.33,101.87,101.53,98.38,56.48,56.42,56.13,56.06,45.67,40.51,37.58,29.49,27.89,22.56,17.15.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 658.2748found 658.2749; purity 95.92% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 3.465min).
Compound BC13: 8-cyclopentyl-2- (2- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) benzoyl) -2, 7-diazaspiro [3.5]Nonan-7-yl) -5-methylpyrido [2,3-d]Pyrimidin-7 (8H) -ones. Yield 52%; 1 H NMR(600MHz,DMSO-d 6 )12.17(s,1H),8.69(s,1H),8.29-8.17(m,2H),7.84-7.77(m,2H),6.77(d,J2.3Hz,1H),6.56(d,J2.3Hz,1H),6.10(s,1H),4.45(dd,J31.3,8.7Hz,1H),4.32(d,J8.7Hz,1H),4.18-4.04(m,3H),3.90(s,3H),3.86(s,3H),3.81-3.74(m,2H),3.69-3.58(m,2H),2.32(s,3H),2.29-2.24(m,5H),1.96(d,J21.3Hz,2H),1.74(d,J15.7Hz,3H),1.65-1.59(m,2H). 13 C NMR(151MHz,DMSO-d 6 )168.52,164.78,163.18,161.44,160.17,158.92,156.98,155.78,153.27,152.62,145.99(d,J10.7Hz),136.02,134.87,128.40,128.16,105.66,105.35,101.88,98.46,62.48,56.48,56.13,52.45,40.52,27.98,27.81,25.84,25.63,17.17.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 684.2905found 684.2904; purity 95.74% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 2.816min).
Compound BC7: n- (2- (4- (8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2, 3-d)]Pyrimidin-2-yl) piperazin-1-ethyl) -4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) benzamide. Yield 47%; 1 H NMR(600MHz,DMSO-d 6 )8.72(s,1H),8.40(s,1H),7.80(d,J7.9Hz,2H),7.61(d,J2.9Hz,1H),7.41(d,J8.0Hz,2H),7.20(d,J2.9Hz,1H),6.13(s,1H),5.86(d,J2.3Hz,1H),4.42(d,J5.8Hz,2H),3.84(d,J6.1Hz,3H),3.81(s,3H),3.66(s,3H),3.42(d,J9.2Hz,3H),2.56-2.53(m,3H),2.35-2.32(m,3H),2.29-2.20(m,2H),1.97-1.89(m,2H),1.75(dd,J12.5,6.4Hz,2H),1.66-1.57(m,2H). 13 C NMR(151MHz,DMSO-d 6 )170.34,163.10,162.89,161.26,160.19,157.15,155.97,153.12,145.86,127.83,127.33,116.97,105.83,97.93,90.05,86.93,56.30,55.33,52.61,46.46,44.23,27.92,25.61,22.56,17.13.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 687.3014found 687.3015; purity 98.28% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 3.545min).
Compound BC8: 8-cyclopentyl-2- ((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) benzoyl) piperidin-3-yl) methyl) amino) -5-methylpyrido [2,3-d]Pyrimidin-7 (8H) -ones. Yield 66%; 1 H NMR(600MHz,DMSO-d 6 )12.13(s,1H),8.44(s,1H),8.20(s,1H),8.00(s,1H),7.49(s,1H),7.32(d,J21.3Hz,1H),6.76(d,J2.4Hz,1H),6.57(s,1H),6.08(s,1H),3.91(s,3H),3.87(s,3H),3.54(d,J69.9Hz,2H),3.05(s,2H),2.76(d,J108.5Hz,2H),2.32(s,3H),2.02-1.68(m,8H),1.52(d,J59.9Hz,5H). 13 C NMR(151MHz,DMSO-d 6 )168.64,164.78,163.11,161.66,161.47,160.18,153.33,139.48,139.37,128.28,127.88,127.17,126.92,116.75,116.22,106.30,105.32,101.86,98.38,56.48,56.13,51.44,48.21,46.03,43.87,42.66,28.68,25.48,24.58,22.56,17.15.HRMS(ESI):[M+Na] + calcd for C 27 H 30 NO 4 658.2748found 658.2787; purity 97.96% (HPLC, agilent 1100, XDB-C18 (5 m,4.6 mm. Times.150 mm), meOH/H) 2 O85/15R t 4.244min).
Example 2
1. Inhibitory Activity of MDA-MB-231, BT549 and MCF-10A cells
And (3) cells: MDA-MB-231 cells (human breast cancer cells), BT549 cells (human breast cancer cells), MCF-10A cells (human normal breast epithelial cells); wherein, MDA-MB-231 cells and BT549 cells are triple negative breast cancer cells.
The experimental method comprises the following steps: centrifuging cells in logarithmic growth phase, discarding supernatant, washing twice with PBS, re-suspending, inoculating into 96-well plate at 2000-3000 cells/100 l/well in culture medium containing 10% foetal calf serum (MDA-MB-231 and DMEM culture medium for MCF-10A; BT549 culture medium for RPMI-1640), and standing at 37deg.C with 5% CO 2 After 24h of incubation, the medium was aspirated, the drug was diluted with fresh medium at the desired concentration and added to a 96-well plate for 72h of co-action, 20 l of MTT (5 mg/mL, PBS) was added to each well, and incubation was continued for another 4h. MTT crystal violet formed by living cells was dissolved in DMSO (150. Mu.L), absorbance values (OD values) of the different wells were measured at 570nm wavelength using an enzyme-labeled instrument, and IC was calculated from the dose-dependent curve 50 Values.
TABLE 2 inhibitory Activity of the inventive Compounds against MDA-MB-231, BT549 and MCF-10A cells a
Note that: a using three independentMean SD representation of the dose response curve of the experiment; b, detecting the cell viability by adopting an MTT method after 72h of treatment.
Table 2 shows that the double-target compounds designed by the invention have better inhibition activity on breast cancer cells and lower toxicity on normal cells; wherein, the inhibition activity of the compounds BC1, BC2, BC3, BC4, BC5, BC6 and BC13 on breast cancer cells is superior to that of a positive control drug, and the inhibition activity of the compound BC13 on breast cancer cells is the most excellent.
2. CDK6 and BRD4 enzyme inhibitory Activity
CDK6/CyclinD3 kinase was purchased from Promega (cat# V4510) and kinase inhibition was detected by ADP-Glo kinase assay (Promega, madison, wisconsin, USA) according to the manufacturer's instructions. The experimental object is histone H1, the final reaction concentration is 0.1mg/mL, the final ATP concentration is 50 mu M, the maximum detection concentration of the tested compound is 10 mu M, the reaction mixture is incubated at 30 for 40min, 25 mu L of stop buffer is added to stop the reaction, three compound wells are arranged according to each compound, each experiment is repeated three times, and the experimental result is expressed as an average value of +/-SEM.
BRD4 enzyme inhibition experiments were performed using the BRD4 bromodomain 1TR-FRET assay kit (item number 600520) obtained from Cayman (Ann Arbor, MI, USA). The sample solutions were diluted with 1 XTR-FRET buffer to prepare samples having concentrations of 3.2. Mu.M, 1.6. Mu.M, 0.8. Mu.M, 0.4. Mu.M, and 0.2. Mu.M, respectively. 5 l of samples of different concentrations were added to each well, 3 replicate wells were set for each concentration gradient, and 10 l of BRD4-BD1 europium chloride solution was added to each well of 384 well plates. After 15min of incubation at room temperature, 5. Mu.L of BRD4 ligand/APC receptor mixture was added to each well and the final volume per well was 20. Mu.L, and the plates were closed and incubated at room temperature. Three duplicate wells were set per compound, each experiment was repeated three times and the experimental results were expressed as mean SEM.
TABLE 3 inhibition of CDK6 and BRD4 enzymes by the compounds of the invention
From table 3, it can be seen that the dual-target compounds of the invention show inhibitory activity against both CDK6 and BRD4, remaining on the nanomolar scale, with the compound BC13 having better inhibitory activity against both enzymes.
The compound disclosed by the invention can not only effectively inhibit proliferation of cancer cells, but also maintain better in-vitro enzyme inhibition activity of CDK6 and BRD4, and has great potential as an antitumor drug.
3. Anti-tumor activity experiment of compound in mice
MDA-MB-231 tumor cells (8X 10) 6 And/or) were suspended in PBS and subcutaneously implanted into 6-8 week old female BALB/c nude mice. The feeding environment was sterile food and water, and was performed under standard laboratory conditions (22.+ -. 2 , 55.+ -. 10% humidity, 12h light/12 h dark cycle). When the tumor volume reaches 80-120mm 3 At this time, mice were randomly divided into 5 groups (5 per group): palbociclib (Palbociclib) group (Palbociclib administered at a dose of 50 mg/kg), JQ-1 group (JQ-1 administered at a dose of 50 mg/kg), BC13 low dose group (compound BC13 administered at a dose of 25 mg/kg), BC13 high dose group (compound BC13 administered at a dose of 50 mg/kg) and Control group (Control). The control group was intraperitoneally injected with an equal volume of the drug-loaded solution, which was a mixed solution of 5% (V/V) DMSO, 25% (V/V) castor oil, and 70% (V/V) physiological saline. All groups were given intraperitoneally at equal volumes every two days for a total of 21 days of treatment. Tumor volume was measured every 2 days with calipers and the mice were weighed and tumor volume was calculated according to the following formula:
tumor volume (mm) 3 ) Length (mm) 3 ) Width x 2 (mm 3 )0.5
After the end of the administration, the mice were sacrificed, the tumors and the various tissue organs required were dissected, the tumors were weighed, and HE staining was performed on the various tissue organs.
The results show that the same dose of compound BC13 has a more pronounced ability to inhibit tumor growth compared to the positive drugs palbociclib and JQ-1 (fig. 1 and 2). In addition, there was no significant change in body weight of mice following compound BC13 dry (fig. 3). The results of HE staining of mice heart, liver, spleen, lung and kidney were not significantly impaired after administration of high dose compound BC13 compared to the control group (fig. 4), indicating low toxicity and safety of compound BC13 in vivo.
Claims (10)
- A cdk6/BRD4 dual-target inhibitor characterized by: a compound selected from the structures shown in formula I:wherein L is selected from-HN- (CH) 2 ) m -NH- m is an integer of 1 to 6, n is an integer of 0 to 6, o is an integer of 0 to 6, p is an integer of 0 to 6, and q is an integer of 0 to 6.
- 2. The CDK6/BRD4 dual-target inhibitor according to claim 1, characterized in that: in the compound with the structure shown in the formula I, L is selected from-HN- (CH) 2 ) m -NH- m is an integer of 2 to 6, n is 0, p is 1, and q is 1.
- A cdk6/BRD4 dual-target inhibitor characterized by: a compound selected from the structures shown in formula I:wherein L is selected fromn is 0 and p is 1.
- A cdk6/BRD4 dual-target inhibitor characterized by: a compound selected from the structures shown below or a pharmaceutically acceptable salt thereof:
- a cdk6/BRD4 dual-target inhibitor characterized by: a compound selected from the structures represented by the formula:
- 6. a method of preparing a CDK6/BRD4 dual-target inhibitor according to claim 1, wherein: the synthetic route is as follows:wherein L is as claimed in claim 1;the method comprises the following steps:step (a), isopropanol is used as a reaction solvent, DIPEA is used as an acid binding agent, and N is used as a catalyst 2 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one and under protectionReflux reaction to obtain intermediate 2;step (b), methylene dichloride is used as a reaction solvent, and a protective group is removed from the intermediate 2 at room temperature in the presence of trifluoroacetic acid to obtain an intermediate 3;step (c), using DCM as a reaction solvent, mixing the intermediate 3 with p-carboxybenzaldehyde and HATU, and reacting at room temperature by using DIPEA as an acid-binding agent to obtain an intermediate 4;step (d) using N, N-dimethylacetamide as a reaction solvent, and using intermediate 4, compound 5 and PTSA, naHSO 3 Adding the mixture into a reaction solvent, and carrying out reflux reaction at 120 for 4-8 hours to obtain the compound with the structure shown in the formula I.
- 7. The method of preparing a CDK6/BRD4 dual-target inhibitor according to claim 6, wherein: in step (a), the 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one andthe molar ratio of (2) is 1:1.5-1:2; the molar ratio of the 2-chloro-8-cyclopentyl-5-methylpyridin-7 (8H) -one to the DIPEA is 1:3-1:4;in the step (b), the molar ratio of the intermediate product 2 to the trifluoroacetic acid is 1:4-1:7;in the step (c), the molar ratio of the intermediate 3 to the p-carboxybenzaldehyde is 1:1.25-1:2; the mol ratio of the intermediate 3 to the HATU is 1:2-1:2.5; the mol ratio of the intermediate 3 to the DIPEA is 1:7-1:15;in the step (d), the molar ratio of the intermediate 4 to the compound 5 is 1:1-1:3; the mol ratio of the intermediate 4 to the PTSA is 1:0.1-1:0.3; intermediate 4 and NaHSO 3 The molar ratio of (2) is 1:1.5-1:3.
- 8. Use of a CDK6/BRD4 dual-target inhibitor according to any one of claims 1-5 in the preparation of a medicament for treating a CDK6/BRD4 mediated disorder.
- 9. Use of a CDK6/BRD4 dual-target inhibitor according to any one of claims 1-5 in the preparation of a medicament for the treatment or prophylaxis of triple negative breast cancer.
- 10. A pharmaceutical composition characterized by: the pharmaceutical composition comprising a dual-target inhibitor of CDK6/BRD4 according to any one of claims 1-5, and a pharmaceutically acceptable carrier.
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