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First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins
Paul D O'Dowd1,2, Graeme P Sullivan3, Daniel A Rodrigues1
1Department of Chemistry, Royal College of Surgeons in Ireland, Dublin 2, Ireland. dgriffith@rcsi.ie.
Chemical Communications (Cambridge, England)
|October 4, 2023
Summary
Researchers developed the first platinum-based proteolysis-targeting chimera (Pt-PROTAC) to degrade specific platinum(II)-binding proteins. This novel metallo-PROTAC effectively targeted thioredoxin proteins in multiple myeloma cells, showing potential for cancer therapy.
Area of Science:
- Biochemistry
- Chemical Biology
- Oncology
Background:
- Proteolysis-targeting chimeras (PROTACs) are emerging therapeutics.
- Targeting intracellular proteins remains a challenge in drug development.
- Platinum(II) compounds are widely used in cancer chemotherapy.
Purpose of the Study:
- To develop the first metallo-PROTAC utilizing platinum(II).
- To investigate the efficacy of a Pt-PROTAC in degrading specific Pt(II)-binding proteins.
- To explore the potential of metallo-PROTACs in cancer therapy and protein identification.
Main Methods:
- Design and synthesis of a novel Pt-PROTAC.
- In vitro degradation assays using multiple myeloma cancer cell lines.
- Target protein identification and validation.
Main Results:
- The Pt-PROTAC successfully degraded thioredoxin-1 and thioredoxin reductase-1.
- Demonstrated selective degradation of target proteins in cancer cells.
- Validated the proof-of-concept for metallo-PROTACs.
Conclusions:
- Metallo-PROTACs represent a new class of targeted protein degraders.
- Pt-PROTACs show promise as chemotherapeutic agents for cancer treatment.
- This approach can aid in identifying novel metal-binding proteins.
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