Protein degradation targeting chimera and application thereof

A protein degradation and chimera technology, applied in the field of chemical medicine, can solve problems such as affecting drug efficacy and poor effect

Active Publication Date: 2021-09-10
JINAN UNIVERSITY
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical drug resistance induced by Bcr-Abl mutation has become an important problem in today's oncology medicine
The second-generation drugs nilotinib and dasatinib can only overcome drug resistance caused by some gene mutations, but they are not effective against Bcr-Abl T315I This most frequently occurring resistance mutation is ineffective
December 2012, overcoming Bcr-Abl T315I Drug-resistant ponatinib has only been approved for marketing in the United States, but its effect on Bcr-Abl E255K / V Mutations in the P-Loop region are less effective
However, small molecule inhibitors targeting kinases cannot avoid secondary mutations again, leading to clinical drug resistance and affecting drug efficacy

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Protein degradation targeting chimera and application thereof
  • Protein degradation targeting chimera and application thereof
  • Protein degradation targeting chimera and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment

[0049] The reagents and raw materials used in the following examples are commercially available unless otherwise specified, and the corresponding Chinese meanings of the English abbreviations of the reagents are as follows:

[0050] NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; DCM: dichloromethane; PE: petroleum ether; EA: ethyl acetate; TMSA: trimethylsilylacetylene; DMF: N , N-dimethylformamide; PMBCl: p-methoxybenzyl chloride; THF: tetrahydrofuran; TFA: trifluoroacetic acid; HATU: 2-(7-azabenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate; DIEA: N,N-diisopropylethylamine; TsCl: 4-toluenesulfonyl chloride.

Embodiment 1

[0051] Example 1: 3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)-4-methyl-N-( Preparation of 4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide (compound 8)

[0052]

[0053] Step a: Preparation of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (Compound 1)

[0054]

[0055] To a solution of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (30 g, 146.3 mmol, 1 equiv) in 1,2-dichloroethane was added NBS (31.2 g, 175.5 mmol, 1.2 equiv ) and AIBN (2.4 g, 14.63 mmol, 0.1 equiv). The reaction mixture was heated at 90 °C overnight. After cooling, water was added to the mixture, the organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by flash chromatography on silica gel (PE:EA=50:1) to give a pale yellow oil (6.1 g, 68%). 1 H NMR (400MHz, DMSO-d 6 )δ8.54(dd, J=8.5,2.5H...

Embodiment 2

[0077] Embodiment 2: the preparation of compound 11 and 12

[0078]

[0079] Step i: tert-butyl 3-(2-(2-(4-(4-(3-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine Base-5-yl)ethynyl)-4-methylbenzamido)-2-(trifluoromethyl)benzyl)piperazin-1-yl)ethoxy)ethoxy)propionate ( Compound 9) Preparation

[0080]

[0081] To compound 8 (400mg, 0.62mmol, 1equiv) and 3-(2-(2-(tosyloxy)ethoxy)ethoxy) propanoic acid tert-butyl ester (316mg, 0.82mmol, 1.3equiv) To a solution of acetonitrile (30ml) was added anhydrous potassium carbonate (173mg, 1.25mmol, 2equiv), and the mixture was magnetically stirred at reflux temperature for 10 hours. After the reaction was finished, filter with suction and wash with CH 2 Cl 2 (2×25 mL), the filtrate was evaporated in vacuo and the residue was distilled under reduced pressure, the residue was purified by flash column chromatography on silica gel (DCM:CH 3 OH=15:1) afforded the product as a white solid (270 mg, 51%). 1 H NMR (400MHz, Chloroform-d)...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a protein degradation targeting chimera with a structure as shown in a general formula (I) defined in the description and application thereof. The protein degradation targeting chimera provided by the invention can effectively inhibit the kinase activity of Bcr-Abl and a Bcr-AblT315I mutant, can inhibit the expression of Bcr-AblT315I in tumor cells, has the function of degrading Bcr-AblT315I, has a better anti-proliferation effect on tumor cells carrying Bcr-Abl or Bcr-AblT315I, and can be used as a potential drug for anti-tumor treatment.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to a protein degradation targeting chimera and its application. Background technique [0002] Tumor is currently the number one killer of human health and life, and its incidence is on the rise. In recent years, although some novel tyrosine protein inhibitors and other targeted new drugs have been developed and marketed, they are still far from meeting the growing needs of clinical cancer patients. The research and development of anti-tumor drugs is still an important research direction in the drug research and development field. As of October 2019, 52 small-molecule protein tyrosine kinases have been approved for marketing by the FDA, and have achieved good tumor treatment effects. [0003] The Bcr-Abl small molecule inhibitor imatinib is the first tumor treatment drug designed and developed rationally after understanding the etiology of cancer, and has achieved re...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/496C07K5/062A61K38/05A61P35/00
CPCC07D471/04C07K5/06034A61P35/00
Inventor 陆小云丁克张章蒋亮王雨婷涂正超
Owner JINAN UNIVERSITY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap