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.