Design and Synthesis of Pyrrolo[3,4-d]pyrimidine-Based ATR Degraders for Effective Treatment of Colorectal Cancer in
Nian-Dong Mao1,2,3, Zi Hui1, Chen-Chen Wang1,2,3
1School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.
Abstract:
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.
Insights
A novel compound, A12, effectively degrades Ataxia telangiectasia and Rad3-related kinase (ATR) and CHK1, showing significant anti-cancer effects in colorectal cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ataxia telangiectasia and Rad3-related kinase (ATR) is a key regulator of the DNA damage response.
- ATR inhibitors are under investigation but lack regulatory approval.
- Targeting ATR offers a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To design and synthesize a novel pyrrolo[3,4-d]pyrimidine compound, A12, as a potent ATR degrader.
- To evaluate the efficacy of A12 as a monotherapy and in combination with cetuximab in colorectal cancer models.
- To assess the safety profile of A12 in preclinical studies.
Main Methods:
- Synthesis of A12, a novel ATR degrader.
- In vitro assessment of ATR and CHK1 degradation in colorectal cancer cells.
- Evaluation of antiproliferative and apoptotic effects of A12.
- In vivo efficacy studies using a LoVo xenograft mouse model.
- Combination therapy studies with A12 and cetuximab.
Main Results:
- A12 effectively induced proteasomal degradation of ATR (DC50: 127 nM) and CHK1 (DC50: 135 nM) in colorectal cancer cells.
- A12 demonstrated potent antiproliferative activity (IC50: 55 nM) and induced apoptosis.
- A12 monotherapy achieved significant tumor growth inhibition (74%) in a LoVo xenograft model without apparent toxicity.
- Combination therapy with A12 and cetuximab enhanced tumor growth inhibition (81%) with a favorable safety profile.
Conclusions:
- A12 is a potent ATR degrader that also degrades CHK1, exhibiting significant anti-cancer activity.
- A12 represents a promising therapeutic strategy for colorectal cancer, potentially applicable to other tumor types.
- Dual ATR and CHK1 degradation via A12 offers a novel approach to cancer therapy.
