N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα)

Dima A. Sabbah; Neka A. Simms; Wang Wang; Yuxiang Dong; Edward L. Ezell; Michael G. Brattain; Jonathan L. Vennerstrom; Haizhen A. Zhong

doi:10.1016/j.bmc.2012.09.059

N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα)

Dima A. Sabbah, Neka A. Simms, Wang Wang, Yuxiang Dong, Edward L. Ezell, Michael G. Brattain, Jonathan L. Vennerstrom, Haizhen A. Zhong

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

25 Scopus citations

Abstract

This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3- carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.

Original language	English (US)
Pages (from-to)	7175-7183
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2012.09.059
State	Published - Dec 15 2012

Keywords

AKT phosphorylation
Apoptosis
Colon cancer
PI3K
Selectivity

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2012.09.059

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N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα). / Sabbah, Dima A.; Simms, Neka A.; Wang, Wang; Dong, Yuxiang; Ezell, Edward L.; Brattain, Michael G.; Vennerstrom, Jonathan L.; Zhong, Haizhen A.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 24, 15.12.2012, p. 7175-7183.

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

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title = "N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα)",

abstract = "This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3- carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.",

keywords = "AKT phosphorylation, Apoptosis, Colon cancer, PI3K, Selectivity",

author = "Sabbah, {Dima A.} and Simms, {Neka A.} and Wang Wang and Yuxiang Dong and Ezell, {Edward L.} and Brattain, {Michael G.} and Vennerstrom, {Jonathan L.} and Zhong, {Haizhen A.}",

note = "Funding Information: This work was partially supported by a FIRE Grant from the University of Nebraska at Omaha. DAS acknowledges Al-Zaytoonah Private University of Jordan, and a Bukey Fellowship from the University of Nebraska Medical Center for financial support. NAS and MGB acknowledge NIH (CA72001 and CA38173) for support. ",

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doi = "10.1016/j.bmc.2012.09.059",

language = "English (US)",

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AU - Sabbah, Dima A.

AU - Simms, Neka A.

AU - Wang, Wang

AU - Dong, Yuxiang

AU - Ezell, Edward L.

AU - Brattain, Michael G.

AU - Vennerstrom, Jonathan L.

AU - Zhong, Haizhen A.

N1 - Funding Information: This work was partially supported by a FIRE Grant from the University of Nebraska at Omaha. DAS acknowledges Al-Zaytoonah Private University of Jordan, and a Bukey Fellowship from the University of Nebraska Medical Center for financial support. NAS and MGB acknowledge NIH (CA72001 and CA38173) for support.

PY - 2012/12/15

Y1 - 2012/12/15

N2 - This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3- carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.

AB - This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3- carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.

KW - AKT phosphorylation

KW - Apoptosis

KW - Colon cancer

KW - PI3K

KW - Selectivity

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JO - Bioorganic and Medicinal Chemistry

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N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα)

Abstract

Keywords

ASJC Scopus subject areas

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