Design and Synthesis of Pyrrolo[3,4-d]pyrimidine-Based ATR Degraders for Effective Treatment of Colorectal Cancer in Mouse Model.

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 A12 based on the pyrrolo[3,4-d]pyrimidine scaffold was designed and synthesized, with the ability not only to induce proteasomal degradation of ATR (DC50: 127 nM, Dmax: 72%) but also of CHK1 (DC50: 135 nM, Dmax: 70%) in several colorectal cancer cells. It exhibits strong antiproliferative activity (IC50: 55 nM) and rapidly triggers apoptosis. In LoVo xenograft mouse model, A12 monotherapy (30 mg/kg) achieved outstanding tumor growth inhibition (TGI: 74%) without apparent toxicity. Combination with A12 (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 A12, which also degrade CHK1 simultaneously, represents as a promising therapeutic strategy for colorectal cancer and potentially other tumor types.