ALK-targeted PROTAC and application thereof

A -CH2-, compound technology, applied in the field of anti-tumor drugs, can solve the problems of decreased kinase activity and anti-tumor activity, and achieve good anti-tumor activity and low toxicity of normal cells

Inactive Publication Date: 2020-01-14
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inventors found that, compared with the positive drug LDK378, the PROTAC molecule formed by linking LDK378 and VHL ligand has a sharp decrease in the kinase activity on ALK and a decrease in anti-tumor activity

Method used

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  • ALK-targeted PROTAC and application thereof
  • ALK-targeted PROTAC and application thereof
  • ALK-targeted PROTAC and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1. Synthesis of L series molecules

[0045]

[0046] (i) Oxalyl chloride, DMF, rf, 2h; (ii) Triethylamine, DCM, rt, 15h (iii) EDCI, Hobt, DCM, rt, 12h

[0047] Synthesis of intermediate P4

[0048]

[0049] The raw material succinic acid (118 mg, 0.1 mmol) was added to SOCL 2 In, add 2 drops of DMF, heat and reflux for 2h. The reaction solution was dried under reduced pressure at normal temperature to obtain product 1.

[0050] Dissolve the product 1 in anhydrous DCM, add pomalidomide and triethylamine, and react at room temperature for 15h. After the reaction was completed, the reaction was quenched with water, extracted three times with EA, the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain intermediate P4.

[0051] 1H NMR (400MHz, DMSO) δ = 8.47 (d, J = 8.1, 1H), 7.82 (dd, J = 8.4, 7.4, 1H), 7.60 (d, J = 6.9, 1H), 5.14 (dd, J = 12.8,5.4,1H), 2.91(ddd,...

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Abstract

The invention relates to ALK-targeted PROTAC and application thereof, and belongs to the technical field of anti-tumor drugs. The invention aims to provide an ALK-targeted PROTAC molecule. The PROTACmolecule has the structural formula which is shown in a formula I. A ligand pomalidomide of CRBN and a derivative of pomalidomide are adopted as a ligand of an E3 ligase, and coupling of an ALK inhibitor LDK378 with the E3 ligase is achieved through linkers of different types and different chain lengths so as to prepare the ALK-targeted PROTAC molecule successfully; through the ALK-targeted PROTACmolecule, target proteins can be targeted effectively, the content of ALK in cells is reduced, and meanwhile, the ALK-targeted PROTAC is characteristics of good anti-tumor activity in vitro and in vivo, low toxicity to normal cells and high efficiency and low toxicity.

Description

technical field [0001] The invention relates to PROTAC targeting ALK and application thereof, belonging to the technical field of antitumor drugs. Background technique [0002] Proteolysis-targeting chimeras (proteolysis-targeting chimeras, PROTACs) are compounds with two heterofunctional ligands connected by a linker: one ligand targets the protein of interest (POI), while the other ligand specifically recruits E3 ligase. When PROTAC binds E3 ligase and target protein to form a ternary complex, by hijacking E3 ligase, PROTAC presents POI with a favorable steric position to promote its ubiquitination, thereby selectively reducing the level of target protein. The advantage of this method is that PROTACs can catalyze multiple rounds of degradation of target proteins, which is the biggest difference between PROTAC molecules and small molecule inhibitors. [0003] Anaplastic Lymphoma Kinase (Anaplastic Lymphoma Kinase, ALK) is a receptor tyrosine kinase associated with three t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00C09K11/06A61K47/65A61K47/62A61K49/00
CPCA61K47/62A61K47/65A61K49/0021A61K49/0056A61P35/00C07D401/14C09K11/06C09K2211/1007C09K2211/1029C09K2211/1044
Inventor 李锐魏于全
Owner SICHUAN UNIV
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