Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras
Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, whic...
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| Published in | ACS central science Vol. 2; no. 12; pp. 927 - 934 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
28.12.2016
|
| Online Access | Get full text |
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| Abstract | Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties. We show here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide derivative which reacts rapidly with a trans-cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC molecule. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncology targets, BRD4 and ERK1/2. ERK1/2 degradation was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degradation. |
|---|---|
| AbstractList | Selective
degradation of proteins by proteolysis targeting chimeras
(PROTACs) offers a promising potential alternative to protein inhibition
for therapeutic intervention. Current PROTAC molecules incorporate
a ligand for the target protein, a linker, and an E3 ubiquitin ligase
recruiting group, which bring together target protein and ubiquitinating
machinery. Such hetero-bifunctional molecules require significant
linker optimization and possess high molecular weight, which can limit
cellular permeation, solubility, and other drug-like properties. We
show here that the hetero-bifunctional molecule can be formed intracellularly
by bio-orthogonal click combination of two smaller precursors. We
designed a tetrazine tagged thalidomide derivative which reacts rapidly
with a
trans
-cyclo-octene tagged ligand of the target
protein in cells to form a cereblon E3 ligase recruiting PROTAC molecule.
The in-cell click-formed proteolysis targeting chimeras (CLIPTACs)
were successfully used to degrade two key oncology targets, BRD4 and
ERK1/2. ERK1/2 degradation was achieved using a CLIPTAC based on a
covalent inhibitor. We expect this approach to be readily extendable
to other inhibitor-protein systems because the tagged E3 ligase recruiter
is capable of undergoing the click reaction with a suitably tagged
ligand of any protein of interest to elicit its degradation.
Tetrazine-tagged thalidomide derivatives undergo click reaction
with
trans
-cyclo-octene-tagged protein ligands in
cells: the resulting click-formed proteolysis-targeting chimeric molecule
elicits ubiquitination and degradation of the target protein. Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties. We show here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide derivative which reacts rapidly with a trans-cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC molecule. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncology targets, BRD4 and ERK1/2. ERK1/2 degradation was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degradation. Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties. We show here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide derivative which reacts rapidly with a -cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC molecule. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncology targets, BRD4 and ERK1/2. ERK1/2 degradation was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degradation. |
| Author | Johnson, Christopher N Lebraud, Honorine Wright, David J Heightman, Tom D |
| AuthorAffiliation | Astex Pharmaceuticals |
| AuthorAffiliation_xml | – name: Astex Pharmaceuticals |
| Author_xml | – sequence: 1 givenname: Honorine surname: Lebraud fullname: Lebraud, Honorine – sequence: 2 givenname: David J surname: Wright fullname: Wright, David J – sequence: 3 givenname: Christopher N surname: Johnson fullname: Johnson, Christopher N – sequence: 4 givenname: Tom D orcidid: 0000-0002-9109-4748 surname: Heightman fullname: Heightman, Tom D email: Tom.Heightman@astx.com |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28058282$$D View this record in MEDLINE/PubMed |
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| Snippet | Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic... Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic... |
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| Title | Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras |
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