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.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Amino Acid Sequence , Antineoplastic Agents/chemical synthesis , Catalytic Domain , Models, Molecular , Molecular Sequence Data , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/chemistry , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacology , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
Two routes to the protected 4-hydroxymethyl-3-methylindole-2-carboxylate fragment 17 of the thiopeptide antibiotic nosiheptide are described starting from methyl 4-methylindole-2-carboxylate 11, itself prepared in two steps, or from 3-amino-4-chlorobenzoic acid 26. The first route can be adapted to the synthesis of a fragment of the related antibiotic glycothiohexide-alpha, the 3,4-bis(hydroxymethyl)indole-2-carboxylate in which the two hydroxymethyl groups are differentiated as in indole 19 or the lactone 20.
