Discovery of the first ataxia telangiectasia and Rad3-related (ATR) degraders for cancer treatment.
Eur J Med Chem
; 267: 116159, 2024 Mar 05.
Article
em En
| MEDLINE
| ID: mdl-38325007
ABSTRACT
The first examples of ataxia telangiectasia and Rad3-related (ATR) PROTACs were designed and synthesized. Among them, the most potent degrader, ZS-7, demonstrated selective and effective ATR degradation in ATM-deficient LoVo cells, with a DC50 value of 0.53 µM. Proteasome-mediated ATR degradation by ZS-7 lasted approximately 12 h after washout in the LoVo cell lines. Notably, ZS-7 demonstrated reasonable PK profiles and, as a single agent or in combination with cisplatin, showed improved antitumor activity and safety profiles compared with the parent inhibitor AZD6738 in a xenograft mouse model of LoVo human colorectal cancer cells upon intraperitoneal (i.p.) administration.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia Telangiectasia
/
Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article