Prospects for the Use of ATR Inhibitors to Treat Cancer 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 1311-1334; doi:10.3390/ph3051311 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Prospects for the Use of ATR Inhibitors to Treat Cancer Jill M. Wagner and Scott H. Kaufmann * Division of Oncology Research, College of Medicine, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA; E-Mail: wagner.jill@ (J.M.W.) * Author to whom correspondence should be addressed; E-mail: kaufmann.scott@ (S.H.K.) Tel.: +1-507-284-8950; Fax: +1-507-293-0107 Received: 31 March 2010; in revised form: 12 April 2010/ Accepted: 19 April 2010/ Published: 28 April 2010 Abstract: ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways. Despite the development of inhibitors of kinases structurally related to ATR, as well as inhibitors of the ATR substrate Chk1, no ATR inhibitors have yet been developed. Here we review the effects of ATR downregulation in cancer cells and discuss the potential for development of ATR inhibitors for clinical use. Keywords: Replication checkpoint; ATR; ATM; chemotherapy; Chk1 Abbreviations: 5-FU, 5-fluorouracil; ATM, ataxia telengiectasia mutated; ATR, ataxia telengiectasia and Rad3-related; ATRIP, ATR-interacting protein; BLM, Bloom helicase; BRCA1, breast cancer (suppressor) 1; Chk1, checkpoint kinase 1; Chk2, checkpoint kinase 2; DSB, double-strand break; HR, homologous recombination; mTOR, mammalian target of rapamycin; NHEJ, non-homologous end joining; PIKK, phosphoinositide 3-kinase related kinase; PRD, PIK regulatory domain; RFC, replication factor C; RPA, replication protein A; ssDNA, single-stranded DNA; TOPBP1, topoisomerase binding protein 1; WRN, Werner’s syndrome protein. 1. Introduction All cells have mechanisms to maintain the integrity of their genomes. Cell cycle checkpoint pathways have evolved to regulate cell cycle progression, DNA replication, and repair of damaged DNA [1,2]. The ataxia t