Design, synthesis, and evaluation of dual EGFR/AURKB inhibitors as anticancer agents for non-small cell lung cancer.
Bioorg Med Chem Lett
; 100: 129612, 2024 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-38199330
ABSTRACT
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are first-line agents for mutant EGFR-positive (mEGFR+) NSCLC. However, secondary resistant mutations develop following therapy that prevent EGFR-TKI binding. The EGFR-TKIs are rendered ineffective in NSCLC expressing EGFR resistant mutations (rmEGFR+). Mutations in Kirsten rat sarcoma virus protein (mKRAS) support persistent signaling downstream of EGFR regardless of EGFR-TKI earlier in the signaling cascade. The EGFR-TKIs are ineffective in mKRAS+ NSCLC. Thus, newer anticancer agents are needed for rmEGFR+ and mKRAS+ NSCLC. Aurora kinase B (AURKB) is a mitosis related kinase that is overexpressed in NSCLC and supports cancer cell proliferation and survival. Literature reports have suggested that AURKB inhibitors if given concurrently with an EGFR-TKI could overcome EGFR-TKI resistance in mKRAS+ NSCLC and rmEGFR + NSCLC, and showed improved anticancer effects compared to current single-targeted EGFR-TKIs. Molecular modeling was used to identify similarities between the kinase pockets of EGFR and AURKB. An overlap was observed for the inactive conformation of EGFR and the active conformation of AURKB. Compounds 3-7 were synthesized as dual EGFR/AURKB inhibitors for mKRAS+ and rmEGFR+ NSCLC. Compounds 5, 6 and 7 were identified as dual EGFR/AURKB inhibitors. Compound 5 demonstrated modest micromolar inhibition of rmEGFR+ NSCLC. All investigated compounds showed moderate inhibition of mKRAS+ NSCLC cells. Compound 7 demonstrated single-digit micromolar inhibition of mKRAS+ NSCLC.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Pulmao
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
/
Neoplasias Pulmonares
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article