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

Sudhakar Manda; Na Keum Lee; Dong-Chan Oh; Jeeyeon Lee

doi:10.3390/molecules25081948

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

Molecules. 2020 Apr 23;25(8):1948. doi: 10.3390/molecules25081948.

Authors

Sudhakar Manda¹, Na Keum Lee¹, Dong-Chan Oh², Jeeyeon Lee¹

Affiliations

¹ College of Pharmacy, Research Institute of Pharmaceutical sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea.
² Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Abstract

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.

Keywords: IGF-1R; PROTACs; Src; anticancer activity; protein degradation.

MeSH terms

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
Molecular Structure
Molecular Targeted Therapy
Proteolysis*
Receptor, IGF Type 1 / metabolism*
Ubiquitin-Protein Ligases / metabolism
Ubiquitination
src-Family Kinases / metabolism*

Substances

Antineoplastic Agents
Ubiquitin-Protein Ligases
Receptor, IGF Type 1
src-Family Kinases

Grants and funding

2018R1A2B2005535 and 2018R1A4A1021703/National Research Foundation of Korea