title: Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors.
abstract: A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Barsanti
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Aversa
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Xianming
authors.initials: X
authors.lastname: Jin
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Elling
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Rama
authors.initials: R
authors.lastname: Jain
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Lin
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rudewicz
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: Sim
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Lorena
authors.initials: L
authors.lastname: Taricani
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
keywords: ATR; CYP3A4 TDI; Fsp3; deuterium; structure-based drug design