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Cereblon ligands and bifunctional compounds comprising the same

a technology of ligands and e3 ligases, applied in the field ofimide-based compounds, can solve the problems of difficult development of ligands of e3 ligases, difficult targeting of protein-protein interactions using small molecules, and encouraging the effect of brd4 inhibition

Inactive Publication Date: 2018-08-02
ARVINAS OPERATIONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a new type of molecule that can be used to target and degrade other proteins in the body. These molecules have a broad range of potential uses, including the treatment of diseases like cancer. The technique involves using a special type of molecule that attaches to a different protein called an E3 Ubiquitin Ligase, which tags the protein for degradation by the body. The patent is important because it provides a new tool for researchers to study how the body regulates protein levels and to potentially develop new treatments for diseases.

Problems solved by technology

On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved.
The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.
Thus, despite the rapid progress of BRD4 inhibitors, the effect of BRD4 inhibition has been encouraging, but less than ideal, as the effect is mostly cytostatic and requires relatively high concentration of inhibitors.
However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents.

Method used

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  • Cereblon ligands and bifunctional compounds comprising the same
  • Cereblon ligands and bifunctional compounds comprising the same
  • Cereblon ligands and bifunctional compounds comprising the same

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Abbreviations

[1602]ACN: acetonitrile[1603]ADDP: 1,1′-(azodicarbonyl)dipiperidine[1604]BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride[1605]BPO: benzoyl peroxide[1606]Cbz: Carbonylbezyloxy[1607]DAST: diethylaminosulfur trifluoride[1608]DBE: 1,2-dibromoethane[1609]DCM: dichloromethane[1610]DEAD: diethyl azodicarboxylate[1611]DIAD: diisopropyl azodicarboxylate[1612]DIBAL: disiobutylaluminium hydride[1613]DIEA or DIPEA: diisopropylethylamine[1614]DMA: N,N-dimethylacetamide[1615]DMF: N,N-dimethylformamide[1616]DMP: Dess-Martin periodinane[1617]EA: ethyl acetate[1618]EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide[1619]HBTU: N,N,N′N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate[1620]HMDS: bis9trimethylsilyl)amine[1621]HMPA: hexamethylphosphoramide[1622]LDA: lithium diisopropylamide[1623]MCPBA: meta-chloroperoxybenzoic acid[1624]MsCl: methanesulfonyl chloride[1625]M.W: microwave[1626]NBS: N-bromosuccinimide[1627]NMP: N-methylpyrrolidone[1628]PCC: pyridinium chlo...

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Abstract

The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present disclosure claims priority to U.S. Provisional Application No. 62 / 452,972, filed 31 Jan. 2017, which is incorporated herein by reference in its entirety.INCORPORATION BY REFERENCE[0002]U.S. patent application Ser. No. 15 / 230,354, filed on Aug. 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719; and U.S. patent application Ser. No. 15 / 801,243, filed on 1 Nov. 2017; and U.S. patent application Ser. No. 15 / 206,497 filed 11 Jul. 2016; and U.S. patent application Ser. No. 15 / 209,648 filed 13 Jul. 2016; and U.S. patent application Ser. No. 15 / 730,728, filed on Oct. 11, 2017; U.S. patent application Ser. No. 15 / 829,541, filed on Dec. 1, 2017; U.S. patent application Ser. No. 15 / 881,318, filed on Jan. 26, 2018; and U.S. patent application Ser. No. 14 / 686,640, filed on Apr. 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. patent application Ser. No. 14 / 792,414, filed on Jul. ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/14C07D417/14C07D471/04C07D471/10C07D487/04C07D495/14C07D498/04A61P35/02
CPCC07D401/14C07D417/14C07D471/04A61P35/02C07D487/04C07D495/14C07D498/04C07D471/10A61K31/454C07D401/04A61P35/00A61K31/4725
Inventor CREW, ANDREW P.BERLIN, MICHAELDONG, HANQINGHOMBERGER, KEITH R.QIAN, YIMINSNYDER, LAWRENCE B.WANG, JINGZIMMERMANN, KURT
Owner ARVINAS OPERATIONS INC
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