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

Lee, B; Kim, DG; Lee, A; Kim, YM; Cui, LJ; Kim, S; Choi, I

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.

Keywords: PROTAC; AIMP2-DX2; lung cancer

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Ligands for Target Protein for PROTAC

PROTAC target protein ligands demonstrate potential therapeutic advantages in lung cancer drug applications. These ligands are specially designed molecules that bind to and recognize key proteins that are overexpressed in lung cancer cells. Once bound to the target protein, the ligand activates the PROTAC mechanism, causing the target protein to be ubiquitinated and degraded, thereby inhibiting the survival and proliferation of lung cancer cells. The design of this targeting ligand makes PROTAC more precise and effective in the treatment of lung cancer. By selecting specific protein targets, highly specific effects on lung cancer cells can be achieved and interference with normal cells can be reduced. This precision is expected to improve treatment effectiveness and reduce adverse effects in patients. Research on the application of PROTAC target protein ligands in lung cancer drugs provides a new direction for the development of personalized treatment and precision medicine, and provides new hope for overcoming the limitations of traditional treatments and improving treatment effects.