Case study: ATR kinase inhibitor

08 APR 2025 Nuvisan Print

Lead identification and optimization using a combination of high-throughput screening and structure-based design

Objective:

In the effort to advance cancer treatment, precision targeting of the DNA damage response (DDR) pathway is opening new possibilities for combating tumors. ATR kinase inhibitors, such as BAY 1895344 (Elimusertib), represent a promising step forward in exploring innovative therapeutic approaches.

ATR kinase is a key mediator of DNA damage signaling and the replication stress response. Inhibition of ATR leads to generation of DNA double strand breaks, ultimately leading to tumor cell death. As part of a project at a third-party company with which they were affiliated at the time, a team of Nuvisan employees developed and preclinically characterized a potent, highly selective, orally available ATR inhibitor by a combined high-throughput screening and structure-based optimization approach.

Case:

BAY 1895344 demonstrates significant efficacy as a monotherapy in preclinical cancer models, particularly in tumors with DDR deficiencies such as ATM mutations and shows synergy when combined with DNA-damaging agents (e.g. carboplatin) or DDR-compromising therapies (e.g. PARP inhibitors like Olaparib). Utilizing ultra-high throughput screening, Elimusertib was identified as a potent molecule with a low-nanomolar inhibitor profile (Wengner, 2020, Figure 6).

In xenograft studies, Elimusertib effectively reduced tumor growth in multiple cancer types, including ovarian, colorectal and prostate cancers. The combinations of Elimusertib with antiandrogens therapy (darolutamide) and external beam radiotherapy further enhanced therapeutic outcomes in hormone-dependent prostate cancer models. These findings support the potential of ATR inhibitors as versatile anticancer agents for personalized combination therapies targeting DNA repair vulnerabilities.

Our solution:

Clinical potential: Elimusertib was under clinical investigation for cancer with DDR defects, representing opportunities for trial support in oncology research.

Combination therapy synergy: Explore protocols that include ATR inhibitors alongside existing chemotherapies or radiotherapies for expanded treatment regimes.

Safety profiling: Tolerability insights from preclinical models highlight critical dose optimization strategies for clinical applications.

Efficient drug discovery: BAY 1895344 exemplifies the use of ultra-high throughput screening to identify potent, selective cancer therapeutics targeting DDR pathways, enabling fast preclinical and clinical progress.

Our case-specific key technologies:

Source:  

Wengner, A. M. et al. The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models. Molecular Cancer Therapeutics 19, 26–38 (2020). (https://dx.doi.org/10.1158/1535-7163.MCT-19-0019) 

Lücking, U. et al. Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. Journal of Medicinal Chemistry 63, 7293–7325 (2020). (https://dx.doi.org/10.1021/acs.jmedchem.0c00369)