Fiche publication
Date publication
mars 2026
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen
,
Pr LIRUSSI Frédéric
Tous les auteurs :
Mao ND, Hui Z, Wang CC, He ML, Li SR, Yu MQ, Ye L, Zhou JW, Wang ZH, Du BQ, Ye GW, Zhang YQ, Yao X, Feng XL, Lirussi F, Garrido C, Gao Y, Luo H, Ye XY
Lien Pubmed
Résumé
Ataxia telangiectasia and Rad3-related kinase (ATR) is a pivotal DNA damage response regulator. While several ATR inhibitors have entered clinical trials, none have yet been approved for therapeutic use. A potent ATR degrader based on the pyrrolo[3,4-]pyrimidine scaffold was designed and synthesized, with the ability not only to induce proteasomal degradation of ATR (DC: 127 nM, : 72%) but also of CHK1 (DC: 135 nM, : 70%) in several colorectal cancer cells. It exhibits strong antiproliferative activity (IC: 55 nM) and rapidly triggers apoptosis. In LoVo xenograft mouse model, monotherapy (30 mg/kg) achieved outstanding tumor growth inhibition (TGI: 74%) without apparent toxicity. Combination with (10 mg/kg) and cetuximab (3 mg/kg) further enhanced efficacy (TGI: 81%) with a favorable safety profile. These findings highlight that ATR degraders such as , which also degrade CHK1 simultaneously, represents as a promising therapeutic strategy for colorectal cancer and potentially other tumor types.
Référence
J Med Chem. 2026 03 5;:
