Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present.

INTRODUCTION

Ataxia telangiectasia and RAD3-related kinase (ATR) is one of the key phosphatidylinositol 3-kinase-related kinase family members important for DNA damage response and repair pathways. Targeting ATR kinase for potential cancer therapy has attracted a great deal of attention to both pharmaceutical industries and academic community.

AREA COVERED: This article surveys the patents published since 2014 aiming to analyze the structural features of scaffolds and the patent space. It also discusses the recent clinical developments and provides perspectives on the challenges and the future directions.

EXPERT OPINION: ATR kinase appears to be a viable drug target for anticancer therapy. Similar to DNA-PK inhibitors, the clinical investigation of an ATRi employs both monotherapy and combination strategy. In the combination strategy, an ATRi is typically combined with a radiation or a targeted drug such as chemotherapy agent poly (ADP-ribose) polymerase (PARP) inhibitor, etc. Diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl to macrocycle are capable of achieving good ATR inhibitory activity and good ATR selectivity over other closely related enzymes. There are eight ATR inhibitors currently being evaluated in clinics, with the hope to get approval in the near future.