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Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-?/? Inhibitors.

ABSTRACT: Dual inhibition of PI3K-? and PI3K-? is an established therapeutic strategy for treatment of hematological malignancies. Reported molecules targeting PI3K-?/? 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-?/? 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-?/? targeting therapeutics.

SUBMITTER: Ferguson FM

PROVIDER: S-EPMC5066161 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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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.

Ferguson Fleur M FM Ni Jing J Zhang Tinghu T Tesar Bethany B Sim Taebo T Kim Nam Doo ND Deng Xianming X Brown Jennifer R JR Zhao Jean J JJ Gray Nathanael S NS

ACS medicinal chemistry letters 20160802 10

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 ...[more]

PMID: 27774127

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