title: Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents.
abstract: DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.
authors.affiliation: Chemistry Department, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, United Kingdom.
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Charrier
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Durrant
authors.forename: Julian M C
authors.initials: JM
authors.lastname: Golec
authors.forename: David P
authors.initials: DP
authors.lastname: Kay
authors.forename: Ronald M A
authors.initials: RM
authors.lastname: Knegtel
authors.forename: Somhairle
authors.initials: S
authors.lastname: MacCormick
authors.forename: Michael
authors.initials: M
authors.lastname: Mortimore
authors.forename: Michael E
authors.initials: ME
authors.lastname: O'Donnell
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Pinder
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.forename: Alistair P
authors.initials: AP
authors.lastname: Rutherford
authors.forename: Paul S H
authors.initials: PS
authors.lastname: Wang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Young
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D055808:Drug Discovery; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013450:Sulfones; D017346:Protein Serine-Threonine Kinases