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

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.