Title:Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy
Volume: 16
Issue: 3
Author(s): Martin Andrs, Jan Korabecny, Eugenie Nepovimova, Daniel Jun, Zdenek Hodny and Kamil Kuca
Affiliation:
关键词:
共济失调毛细血管扩张症Rad3相关激酶（ATR），癌症，化疗增敏，DNA损伤应答，磷脂酰肌醇-3-相关蛋白激酶（PIKK），辐射敏化，合成致死。
摘要: The main aim of current cancer research is to find a way to selectively affect the tumor
cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a
member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for
achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling
pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy,
ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also
resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of
ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells
through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase
have been developed to date. However, those which have been developed provide great promise, and are under evaluation
in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors
and the medicinal chemistry efforts which resulted in their identification.
