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

Fleur M. Ferguson; Jing Ni; Tinghu Zhang; Bethany Tesar; Taebo Sim; Nam Doo Kim; Xianming Deng; Jennifer R. Brown; Jean J. Zhao; Nathanael S. Gray

doi:10.1021/acsmedchemlett.6b00209

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

Fleur M. Ferguson, Jing Ni, Tinghu Zhang, Bethany Tesar, Taebo Sim, Nam Doo Kim, Xianming Deng, Jennifer R. Brown, Jean J. Zhao, Nathanael S. Gray

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Pages (from-to)	908-912
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	7
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00209
Publication status	Published - 2016 Oct 13

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

Keywords

PI3K-γ
PI3K-δ
kinase inhibitor
p110-γ
p110-δ
phosphatidylinositol-4,5-bisphosphate 3-kinase-delta

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.6b00209

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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.",

keywords = "PI3K-γ, PI3K-δ, kinase inhibitor, p110-γ, p110-δ, phosphatidylinositol-4,5-bisphosphate 3-kinase-delta",

author = "Ferguson, {Fleur M.} and Jing Ni and Tinghu Zhang and Bethany Tesar and Taebo Sim and Kim, {Nam Doo} and Xianming Deng and Brown, {Jennifer R.} and Zhao, {Jean J.} and Gray, {Nathanael S.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = oct,

day = "13",

doi = "10.1021/acsmedchemlett.6b00209",

language = "English",

volume = "7",

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T1 - 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

AU - Ferguson, Fleur M.

AU - Ni, Jing

AU - Zhang, Tinghu

AU - Tesar, Bethany

AU - Sim, Taebo

AU - Kim, Nam Doo

AU - Deng, Xianming

AU - Brown, Jennifer R.

AU - Zhao, Jean J.

AU - Gray, Nathanael S.

PY - 2016/10/13

Y1 - 2016/10/13

N2 - 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.

AB - 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.

KW - PI3K-γ

KW - PI3K-δ

KW - kinase inhibitor

KW - p110-γ

KW - p110-δ

KW - phosphatidylinositol-4,5-bisphosphate 3-kinase-delta

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U2 - 10.1021/acsmedchemlett.6b00209

DO - 10.1021/acsmedchemlett.6b00209

M3 - Article

AN - SCOPUS:84991449945

SN - 1948-5875

VL - 7

SP - 908

EP - 912

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 10

ER -

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

Bibliographical note

Keywords

ASJC Scopus subject areas

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