Synthesis and discovery of the first potent proteolysis targeting chimaera (PROTAC) degrader of AIMP2-DX2 as a lung cancer drug.
J Enzyme Inhib Med Chem
; 38(1): 51-66, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-36305287
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pulmonares
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article