title: Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors.
abstract: Dual inhibition of PI3K-δ and PI3K-γ is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-δ/γ selectively are chemically similar and based upon isoquinolin-1(2H)-one or quinazolin-4(3H)-one scaffolds. Here we report a chemically distinct series of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-one scaffold with comparable biochemical potency and cellular effects on PI3K signaling. We envisage these molecules will provide useful leads for development of next-generation PI3K-δ/γ targeting therapeutics.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Fleur M
authors: FM
authors: Ferguson
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Jing
authors: J
authors: Ni
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Tinghu
authors: T
authors: Zhang
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
authors: Bethany
authors: B
authors: Tesar
authors: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors: Taebo
authors: T
authors: Sim
authors: Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Republic of Korea.
authors: Nam Doo
authors: ND
authors: Kim
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Xianming
authors: X
authors: Deng
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
authors: Jennifer R
authors: JR
authors: Brown
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Jean J
authors: JJ
authors: Zhao
authors: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors: Nathanael S
authors: NS
authors: Gray
keywords: PI3K-γ; PI3K-δ; kinase inhibitor; p110-γ; p110-δ; phosphatidylinositol-4,5-bisphosphate 3-kinase-delta