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WEE1 protein degradation agent

A protein kinase, C1-C6 technology, applied in the field of chemistry, can solve the problems of genome instability chromosome, mitotic catastrophe, clinical toxicity and side effects, etc.

Inactive Publication Date: 2021-09-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Theoretically, by inhibiting the activity of WEE1 protein kinase, the DNA damage of these p53-deficient tumor cells cannot be repaired in time and enters the M phase, resulting in genome instability and chromosome loss, triggering mitotic catastrophe, and leading to tumor cell apoptosis
Although AZD1775 has made some clinical research progress as a WEE1 protein target inhibitor, there are still some application limitations including obvious clinical side effects, such as nausea, fatigue, thrombocytopenia, and insufficient targeting, etc., as has been proven AZD1775 has dual-target inhibitory effect on PLK1 / WEE1

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] Embodiment 1: the synthetic route of intermediate S15

[0302] Step 1: Synthesis of Compound S3

[0303]

[0304] Compound S1 (10.0 g, 67.5 mmol) and compound S2 (9.40 g, 70.9 mmol) were added to 110 mL of toluene solution, the reaction system was heated to reflux, and reacted for 18 hours. After the detection reaction was completed, it was cooled to room temperature, filtered, washed with n-hexane, and the white solid product was collected and spin-dried to obtain compound S3 (16.1 g, 91% yield). 1 H NMR (400MHz, DMSO) δ 9.87 (s, 1H), 7.95 (d, J=3.2Hz, 4H), 1.45 (s, 9H).

[0305] Step 2: Synthesis of Compound S5

[0306]

[0307] Compound S3 (16.1g, 61.2mmol), potassium carbonate (16.1g, 116mmol) and benzyltriethylammonium chloride (1.39g, 6.12mmol) were added to 110mL of acetonitrile solvent and stirred for 5 minutes, then compound S4 (8mL ,91.8mmol) was added into the reaction system and reacted at room temperature for 18 hours. After the detection reaction...

Embodiment 2

[0330] Embodiment 2: the general synthetic route of compound 1-3

[0331]

[0332] The synthetic route of compound 1:

[0333] Step 1: Synthesis of Compound S18

[0334]

[0335] Compounds S13 (250 mg, 0.51 mmol) and S17 (148 mg, 0.62 mmol) were added to 10 mL of DMF solution. After the system was completely dissolved, potassium carbonate (141 mg, 1.02 mmol) was added, and the temperature was raised to 60°C for 6 hours. After the reaction was completed, 100 mL of water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain yellow solid compound S18 (220 mg, 67% yield). 1 H NMR(400MHz,DMSO)δ10.17(s,1H),8.83(d,J=1.0Hz,1H),8.05(s,1H),7.75(d,J=7.3Hz,1H),7.65-7.46 (m,3H),6.92(d,J=7.6Hz,2H),6.83(s,1H),5.66(dd,J=14.5,8.9Hz,1H),5.33(s,1H),4.99(d, J=10...

Embodiment 3

[0344] Embodiment 3: the general synthetic route of compound 4-7

[0345]

[0346] The synthetic route of compound 4:

[0347] Step 1: Synthesis of compound S21

[0348]

[0349] Compounds S16 (1 g, 3.62 mmol) and S20 (630 mg, 3.62 mmol) were added to 10 mL of DMF solution, DIPEA (1.5 mL) was added under nitrogen protection, and the reaction system was heated to 90°C for 12 hours. After the reaction was completed, 100 mL of water was added to the system, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain yellow solid compound S21 (1.17 g, 75% yield). 1 H NMR (400MHz, DMSO) δ11.09(s, 1H), 7.57(t, J=7.3Hz, 1H), 7.08(d, J=8.4Hz, 1H), 7.02(d, J=6.6Hz, 1H ),6.91(s,1H),6.66(s,1H),5.05(d,J=9.1Hz,1H),3.29(t,J=12.3Hz,2H),3.00(...

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Abstract

The invention provides a WEE1 protein degradation agent. Specifically, the invention provides a compound as shown in a formula V, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, Y-L-MWEE1 (V), in which MWEE1 is a WEE1 binding part capable of being bound with WEE1 protein kinase; the Y is an E3 ubiquitin ligase ligand part; and L is a linking group.

Description

technical field [0001] The present invention belongs to the field of chemistry. Specifically relates to a WEE1 protein degradation agent. Background technique [0002] The uncontrolled proliferation of tumor cells is the basic biological feature of malignant tumors, involving cell cycle regulation mechanisms and changes in cell conduction pathways for DNA damage repair. Related studies have pointed out that cell cycle regulatory proteins are closely related to tumorigenesis. WEE1 protein is a cell cycle regulatory protein. As one of the important members of the serine / threonine protein kinase family, WEE1 protein can block the transition from G2 phase to M phase by regulating the phosphorylation state of CDK1 and affecting its combination with CyclinB. This in turn ensures DNA replication accuracy and chromatin integrity. Therefore, WEE1 protein is a key protein kinase involved in cell cycle G2 / M checkpoint and DNA damage repair process. On the other hand, in normal cell ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02
CPCC07D487/04A61P35/00A61P35/02
Inventor 李佳吕伟肖栋槐周宇波刘婕妤胡小蓓王培培
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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