Novel ATR Inhibitor BAY 1895344: Potency, Selectivity, and Therapeutic Potential in Preclinical Tumor Models

3 June 2024
The DNA damage response (DDR) in eukaryotic cells is a complex signaling mechanism that safeguards genome integrity. DNA damage triggers DDR pathways, leading to cell cycle halt, translation suppression, DNA repair activation, cell survival, or apoptosis. Kinases like ATR play a crucial role in DDR by responding to various DNA damages, including double-strand breaks and replication stress. Targeting ATR kinase activity could be a promising anti-cancer strategy, especially in tumors with heightened DNA damage or deficiencies in repair mechanisms.

The collaborative efforts of medicinal chemistry, pharmacology, DMPK, and computational chemistry have led to the discovery of a potent and selective ATR inhibitor, BAY 1895344. This compound and its lead predecessor, BAY-937, are naphthyridine derivatives with unique structural features. BAY-937 showed significant ATR inhibition in vitro and high kinase selectivity, effectively reducing tumor cell proliferation. It also demonstrated activity in xenograft studies, albeit with some limitations such as low solubility and bioavailability.

Through extensive optimization, BAY 1895344 emerged as an orally available ATR inhibitor with improved aqueous solubility and bioavailability. It exhibits potent ATR inhibition and effectively halts the proliferation of a wide range of human tumor cell lines. BAY 1895344 also showed no activity in the hERG patch-clamp assay and displayed remarkable efficacy in both monotherapy and combination with DNA damage-inducing therapies in preclinical tumor models. The clinical trial for BAY 1895344 was scheduled to begin in early 2017.

The research was presented at the American Association for Cancer Research Annual Meeting in 2017 by a team led by Ulrich T. Luecking and published in the Cancer Research journal.

How to Use Synapse Database to Search and Analyze Translational Medicine Data?

The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

图片包含 应用程序

描述已自动生成

Click on the image below to go directly to the Translational Medicine search interface.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成