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Compound for selectively degrading CDK subtype in targeted manner and application thereof

A compound and selective technology, applied in the field of biomedicine, can solve the problems of serious toxicity, poor treatment effect, hindering clinical development, etc., and achieve the effect of preventing proliferation

Inactive Publication Date: 2020-03-31
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Small molecule CDK inhibitors have been used in clinical studies for the treatment of various cancers, including but not limited to acute myeloid leukemia (AML), breast cancer (BC), non-small cell lung cancer (NSCLC) and prostate cancer (PC); but The treatment effect is poor and the toxicity is severe, hindering its clinical development

Method used

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  • Compound for selectively degrading CDK subtype in targeted manner and application thereof
  • Compound for selectively degrading CDK subtype in targeted manner and application thereof
  • Compound for selectively degrading CDK subtype in targeted manner and application thereof

Examples

Experimental program
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Effect test

Embodiment

[0111] One, the preparation of each intermediate

[0112] 1) Intermediate 1 can be purchased directly, CAS No.: 844442-38-2;

[0113] 2) The synthetic route of intermediate 2 is as follows:

[0114]

[0115] The specific preparation method is: take 5mmol 4-(4-aminobenzyl) piperazine-1-tert-butyl carboxylate CAS No: 304897-49-2 and 7.5mmol HATU and dissolve it in 30mL DMF, then add 10mmol DIPEA and 5.5mmol 4-nitropyrazole-3-carboxylic acid CAS No: 5334-40-7, reacted at room temperature for 12h. The reaction was quenched with water, extracted three times with ethyl acetate, and then passed through a silica gel column with petroleum ether: ethyl acetate 3:1 to obtain compound A with a yield of 76%.

[0116] Weigh 2mmol of Compound A and dissolve in 10mL of ethanol, then add 6mmol of reduced iron powder and 3mmol of ammonium chloride, heat up to 80°C and reflux for 6h. Pad Celite suction filter the reaction solution, then spin the reaction solution to dryness, and use dichlo...

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Abstract

The invention discloses a compound for selectively degrading a CDK subtype in a targeted manner, and belongs to the field of biomedicine. The compound is a compound shown as a formula I or a stereoisomer, a geometrical isomer, a tautomer, a nitrogen oxide compound, a hydrate, a solvent compound, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and can selectively degrade CDK2or CDK2 / 9 so as to block the synthesis process of DNA and achieve the proliferation of cancer cells, wherein certain compounds capable of selectively degrading CDK subtypes in the targeted manner canalso down-regulate signal channels including proto-oncogene products c-MYC and MCL-1, can strongly inhibit the proliferation of cancer cells, and have a potential treatment effect. X-Y-Z Formula I isperformed, wherein: X represents a cyclin kinase inhibitor, Z represents a CRBN ligand, Y represents a chain linking X and Z, and X is a structure as shown in a formula II or a formula III.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a compound selectively targeting and degrading CDK subtypes and an application thereof. Background technique [0002] Cyclin-dependent kinase is abbreviated as CDK in English, and members of the CDK family have different functions. The development of molecules targeting CDK has application prospects in various tumors. One type of CDK subtype, including CDK2, CDK4, and CDK6, is involved in the regulation of eukaryotic cell cycle checkpoints; the other type, such as CDK7, 8, 9, is involved in the regulation of transcription and translation; [0003] CDK2 / 9 forms an active complex with cyclin D during the cell cycle, and cyclin D phosphorylates retinoblastoma protein (pRb), thereby reducing the inhibition of the activity of E2F family transcription factors. In late G1, CDK2 binds to cyclin E, further phosphorylates Rb protein, effectively releases the inhibition of E2F, and a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D487/04A61K31/497A61K31/444A61P35/00
CPCA61P35/00C07D401/14C07D487/04
Inventor 周飞陈元伟
Owner SICHUAN UNIV
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