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

The ATR kinase plays a key role in
the DNA damage response by activating
essential signaling pathways of DNA damage repair, especially in response
to replication stress. Because DNA damage and replication stress are
major sources of genomic instability, selective ATR inhibition has
been recognized as a promising new approach in cancer therapy. We
now report the identification and preclinical evaluation of the novel,
clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts
focusing on potency, selectivity, and oral bioavailability led to
the discovery of the potent, highly selective, orally available ATR
inhibitor BAY 1895344, which exhibited strong monotherapy efficacy
in cancer xenograft models that carry certain DNA damage repair deficiencies.
Moreover, combination treatment of BAY 1895344 with certain DNA damage
inducing chemotherapy resulted in synergistic antitumor activity.
BAY 1895344 is currently under clinical investigation in patients
with advanced solid tumors and lymphomas (NCT03188965).