Synthesis and discovery of the first potent proteolysis targeting chimaera (PROTAC) degrader of AIMP2-DX2 as a lung cancer drug

Bo Ra Lee, Dae Gyu Kim, Aram Lee, Young Mi Kim, Lianji Cui, Sunghoon Kim, Inhee Choi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

ARS-interacting multifunctional proteins 2 (AIMP2) is known to be a powerful tumour suppressor. However, the target AIMP2-DX2, AIMP2-lacking exon 2, is often detected in many cancer patients and cells. The predominant approach for targeting AIMP-DX2 has been attempted via small molecule mediated inhibition, but due to the lack of satisfactory activity against AIMP2-DX2, new therapeutic strategies are needed to develop a novel drug for AIMP2-DX2. Here, we report the use of the PROTAC strategy that combines small-molecule AIMP2-DX2 inhibitors with selective E3-ligase ligands with optimised linkers. Consequently, candidate compound 45 was found to be a degrader of AIMP2-DX2. Together, these findings demonstrate that our PROTAC technology targeting AIMP2-DX2 would be a potential new strategy for future lung cancer treatment.

Original languageEnglish
Pages (from-to)51-66
Number of pages16
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume38
Issue number1
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

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