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

Molecules (Apr 2020)

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

Affiliations

Sudhakar Manda: College of Pharmacy, Research Institute of Pharmaceutical sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
Na Keum Lee: College of Pharmacy, Research Institute of Pharmaceutical sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea
Dong-Chan Oh: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea
Jeeyeon Lee: College of Pharmacy, Research Institute of Pharmaceutical sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea

DOI: https://doi.org/10.3390/molecules25081948
Journal volume & issue: Vol. 25, no. 8
p. 1948

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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