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Erlotinib-based targeted degradation EGFR (epidermal growth factor receptor) protein small molecule compound as well as preparation method and application thereof

A compound and targeted technology, applied in the fields of medical preparations containing active ingredients, organic chemistry, drug combinations, etc., can solve the problems of limited inhibitory effect and drug resistance, and achieve great application prospects, good anti-tumor activity, excellent The effect of EGFR protein degradation

Active Publication Date: 2021-11-05
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the currently used EGFR inhibitors have limited inhibitory effects, and there are certain drug resistance problems. Therefore, the development of a compound that can degrade EGFR protein has extremely important pharmaceutical value

Method used

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  • Erlotinib-based targeted degradation EGFR (epidermal growth factor receptor) protein small molecule compound as well as preparation method and application thereof
  • Erlotinib-based targeted degradation EGFR (epidermal growth factor receptor) protein small molecule compound as well as preparation method and application thereof
  • Erlotinib-based targeted degradation EGFR (epidermal growth factor receptor) protein small molecule compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Preparation of E3 Ligand Small Molecule Compound (Compound 6)

[0050] Preparation of compound 6a:

[0051]

[0052] Compound 1a (100mmol) (n=1) was dissolved in 30mL DCM, Et 3 N (200mmol), TsCl (140mmol) was dissolved in 70mL DCM, and dropped into the reaction solution under ice-bath conditions. After overnight reaction, TLC detection (PE:EA=1:2) raw material reaction is complete, product R f = 0.3. Suction filter the reaction solution, wash the filter cake with a small amount of DCM, adjust the pH of the filtrate to neutral with 6N hydrochloric acid, add an appropriate amount of water, extract the aqueous phase twice with DCM, combine the organic phases, concentrate under reduced pressure, and obtain the compound after separation by column chromatography 2a, 40.7% yield.

[0053] Dissolve the obtained compound 2a in 100mL DMF, add NaN at room temperature 3 (100mmol), the reaction was carried out at an oil bath temperature of 100°C. After reacting f...

Embodiment 2

[0065] Embodiment 2: Preparation of PROTACs compound ALP-1

[0066]

[0067] Compound 6a (0.11 mmol) and erlotinib 7 (0.11 mmol) prepared in Example 1 were dissolved in 1 mL of DMSO, and the stirring was started. Copper sulfate pentahydrate (0.02mmol) and vitamin C (0.04mmol) were dissolved in 0.5mL water and added to the reaction system, and reacted at 50°C for 4h. It was detected by TLC (EA:MeOH=10:1) that the reaction of raw materials was complete. Added water, extracted with EA, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound ALP-1 with a yield of 70%.

[0068] 1 H NMR (500MHz, DMSO-d 6 )δ11.19(s,1H),10.29(s,1H),9.61(s,1H),8.67(d,J=8.4Hz,1H),8.52(s,1H),8.47(s,1H), 8.30(s,1H),7.95(s,1H),7.88(d,J=8.1Hz,1H),7.84–7.77(m,1H),7.58(d,J=7.2Hz,1H),7.53(d ,J=7.7Hz,1H),7.43(t,J=7.9Hz,1H),7.20(s,1H),5.15(dd,J=12.9,5.4Hz,1H),4.58(t,J=5.1H...

Embodiment 3

[0069] Embodiment 3: Preparation of PROTACs compound ALP-2

[0070]

[0071] Compound 6b (0.35 mmol) and erlotinib 7 (0.35 mmol) prepared in Example 1 were dissolved in 2 mL of DMSO, and stirring was started. Copper sulfate pentahydrate (0.06mmol) and vitamin C (0.14mmol) were dissolved in 2mL of water and added to the reaction system, and reacted at 50°C for 5h. TLC detection (EA:MeOH=10:1) raw materials reacted completely, added water, extracted with EA, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound ALP-2 , yield 72%.

[0072] 1 H NMR(500MHz,DMSO-d6)δ11.18(s,1H),10.33(s,1H),9.60(s,1H),8.70(d,J=8.4Hz,1H),8.54(s,1H) ,8.47(s,1H),8.28(s,1H),7.95(s,1H),7.90(d,J=8.0Hz,1H),7.87–7.82(m,1H),7.61(d,J=7.3 Hz,1H),7.54(d,J=7.7Hz,1H),7.45(t,J=7.9Hz,1H),7.22(s,1H),5.16(dd,J=12.9,5.4Hz,1H), 4.59(t, J=5.1Hz, 2H), 4.30(dt, J=14.2, 4.5Hz, 4H), 4.17...

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Abstract

The invention provides an erlotinib-based targeted degradation EGFR (epidermal growth factor receptor) protein small molecule compound as well as a preparation method and application thereof. The compound (I) or pharmaceutically acceptable salt or hydrate thereof and a pharmaceutical composition containing the compound can be applied to preparation of medicines for preventing or / and treating cancers. Pomalidomide is selected as a part, combined with E3 ligase, in PROTACs, erlotinib is selected as a targeted EGFR small-molecule compound, the two parts are connected by a proper connecting chain to construct the PROTACs, and in-vitro antitumor activity test and in-vitro EGFR protein degradation activity show that the compound disclosed by the invention shows good antitumor activity, and can be used for preparing the targeted EGFR small-molecule compound. The small molecule compound shows an excellent EGFR protein degradation effect, can be used for preventing or / and treating various cancers, and has a huge application prospect in the field of medicines.

Description

technical field [0001] The invention relates to a compound targeting to degrade EGFR protein, its preparation method and application. Background technique [0002] The ubiquitin-proteasome system (UPS) is the main pathway for intracellular protein degradation, and it is involved in the degradation of more than 80% of intracellular proteins. UPS is a multi-step reaction process involving many different proteins. Proteins are first Ubiquitin (polypeptide) tag is then recognized and degraded by the proteasome. [0003] The system consists of ubiquitin, ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2, ubiquitin ligase E3, proteasome and its substrate (protein). The process of UPS specific protein degradation is divided into two stages: (1) protein substrate ubiquitination: ubiquitin molecules are powered by APP, activated by E1 and transferred to E2, and then combined with specific protein substrates through E3; (2) ) Degradation of protein substrates: Ubiquiti...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/517A61P35/00A61P35/02
CPCC07D401/14A61P35/00A61P35/02
Inventor 张兴贤王文冰
Owner ZHEJIANG UNIV OF TECH
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