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Compound for degrading FAK (Focal Adhesion Kinase) protein in targeting manner and application thereof

A compound, hydrate technology, applied in the field of biomedicine

Inactive Publication Date: 2018-11-13
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, new drugs that can effectively inhibit or degrade FAK protein have yet to be developed

Method used

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  • Compound for degrading FAK (Focal Adhesion Kinase) protein in targeting manner and application thereof
  • Compound for degrading FAK (Focal Adhesion Kinase) protein in targeting manner and application thereof
  • Compound for degrading FAK (Focal Adhesion Kinase) protein in targeting manner and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0190] (1) Preparation of Intermediate 1a

[0191]

[0192] Add 2 g of p-phenylenediamine, 954 μl of propiolic acid, and 15 ml of chloroform into a 250 ml round-bottom flask, add anhydrous DMF until completely dissolved, cool to zero, and add 3.18 g of DCC in 20 ml of chloroform. Stir at zero for 1 hour, filter to obtain a clear filtrate, and then use DCM:MeOH=20:1 to pass through a silica gel column to obtain intermediate 1a. 1 H-NMR (400MHz, DMSO-d 6 ,ppm):10.35(s,1H),7.24(d,J=8.60Hz,2H),6.50(d,J=8.64Hz,2H),4.97(s,2H),4.25(s,1H).LC -MS: calculated for C 9 h 9 N 2 O[M+H] + :161.06, found 161.28.

[0193] (2) Preparation of Intermediate 2a

[0194]

[0195]Add 2 grams of N-methylmethanesulfonamide, 30 milliliters of anhydrous DMF and 2.1 grams of potassium tert-butoxide into a 100 milliliter round bottom flask, stir at room temperature for 20 minutes, then add 2.2 grams of 2-fluoro-3-cyanopyridine, The reaction was refluxed for 3 hours, quenched with water, extra...

Embodiment 1

[0205] The preparation of compound shown in embodiment 1 formula 1~38

[0206]

[0207] Add 17 mg of Pomalidomide terminal derivatives, 20 mg of intermediate 5a, 7 mg of CuSO in a 5 ml round bottom flask 4 , 23mg sodium ascorbate, 0.1ml water and 0.8ml tert-butanol. After stirring at 70°C for 6 hours, it was washed with water and extracted with DCM. The compound represented by formula 1 was obtained by passing through a silica gel column with dichloromethane:methanol=30:1, and the yield was 61%.

[0208] 1 H-NMR (400MHz, CDCl 3 ,ppm):8.88(s,1H),8.43(dd,J=1.80Hz,J=4.68Hz,1H),8.27(s,1H),8.18(s,1H),7.81(d,J=7.84Hz ,1H),7.59-7.46(m,6H),7.25(m,1H),7.09(d,J=7.04Hz,2H),6.86(d,J=8.52Hz,1H),6.46(t,J= 5.28Hz, 1H), 6.04(s, 1H), 4.95-4.88(m, 3H), 4.65(q, J=4.52Hz, 2H), 3.97(t, J=4.68Hz, 2H), 3.71(t, J=5.12Hz, 2H), 3.46(q, J=5.48Hz, 2H), 3.28(s, 3H), 3.07(s, 3H), 2.76-2.60(m, 3H), 2.10-2.00(m, 1H ).LC-MS: calculated for C 39 h 39 f 3 N 13 o 8 S[M+H] + :906.26, found 906.88....

Embodiment 2

[0228] Embodiment 2 The degradative activity of compound of the present invention to FAK

[0229]The compound of the present invention has a strong degradation activity to FAK, and the small molecular compound represented by formulas 1-10 is taken as an example to test below.

[0230] Cell seeding and small molecule compound treatment:

[0231] Digest PA1 cells with 90% cell confluency with 0.25% trypsin at 37°C for 1 minute, add Mycos'5A medium containing 10% FBS to stop the digestion and pipette into a single cell suspension, 15 ml centrifuge tube Collect single cells, centrifuge at 800rpm for 3 minutes, resuspend the cells with fresh medium, and count the number of cells on a cell counting plate. Cells were seeded in 24-well plates at a cell number of 800k per well.

[0232] After 12-24 hours, add the small molecular compound to be tested (1000x) for treatment, and 2 Incubate for 8 hours in the incubator. After 8 hours of compound treatment, cells were harvested and pro...

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Abstract

The invention provides a compound. The compound is a compound shown as a formula I or a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, a solvate, a metabolic product, pharmaceutically acceptable salt or a prodrug thereof: X-Y-Z (formula I), wherein X represents a ligand of FAK protein, Z represents ligand of E3 ligase and Y represents a chain for connecting the X and the Z.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular, the present invention relates to compounds targeted to degrade FAK protein and applications thereof. Background technique [0002] FAK protein, also known as PTK2, is encoded by the PTK2 gene. FAK kinase plays an important role in cell adhesion, including the adhesion between cells and the interaction between cells and the surrounding environment, and FAK also plays an important role in the movement of cells to the surrounding environment. There is evidence that when the function of the FAK kinase is blocked, the metastatic properties of breast cancer are greatly reduced. [0003] The mRNA level of FAK is highly expressed in about 37% of ovarian cancer cells and about 26% of breast cancer cells. Since FAK is involved in the regulation of various tumors, inhibitors against FAK have also been developed one after another. Including PF-228, PF-271, Y15 (1,2,4,5-benzonetetraamine t...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/506A61P35/00
CPCA61P35/00C07D401/14
Inventor 饶燏周光飚孙永汇吴越高红英
Owner TSINGHUA UNIV
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