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 Andrew Zhong

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)7175-7183
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2012

Fingerprint

1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Phosphotransferases
Cell growth
Apoptosis
Growth
carbostyril
2-phenyl-4-oxohydroquinoline
Lead

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

Cite this

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 Andrew.

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

Research output: Contribution to journalArticle

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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 Andrew

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