Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src

Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src

A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various...

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Veröffentlicht in:Molecules (Basel, Switzerland) Switzerland), 2020-04, Vol.25 (8), p.1948
Hauptverfasser: Manda, Sudhakar, Lee, Na Keum, Oh, Dong-Chan, Lee, Jeeyeon
Format: Artikel
Sprache:eng
Schlagworte:
anticancer activity
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Movement - drug effects
Chemistry Techniques, Synthetic
Dose-Response Relationship, Drug
Drug Design
Drug Development
Humans
IGF-1R
Molecular Structure
Molecular Targeted Therapy
PROTACs
protein degradation
Proteolysis
Receptor, IGF Type 1 - metabolism
Src
src-Family Kinases - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Zusammenfassung:A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a-b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1-5 μM) in various cellular assays.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25081948