Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt

Alan P. Kozikowski, Haiying Sun, John Brognard, Phillip A. Dennis

Research output: Contribution to journalArticle

Abstract

The synthesis from l-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream of ras such as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.

Original languageEnglish (US)
Pages (from-to)1144-1145
Number of pages2
JournalJournal of the American Chemical Society
Volume125
Issue number5
DOIs
StatePublished - Feb 5 2003
Externally publishedYes

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Protein-Serine-Threonine Kinases
Phosphatidylinositols
Phosphotransferases
Chemical activation
Phosphoinositide Phospholipase C
Carbonates
Hydroxyl Radical
Ether
Lipids
Ethers
Lung Neoplasms
Phosphates
Ligands
Cells
Proteins
Degradation
Substrates
Neoplasms
Therapeutics
quebrachitol

ASJC Scopus subject areas

  • Chemistry(all)

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Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. / Kozikowski, Alan P.; Sun, Haiying; Brognard, John; Dennis, Phillip A.

In: Journal of the American Chemical Society, Vol. 125, No. 5, 05.02.2003, p. 1144-1145.

Research output: Contribution to journalArticle

Kozikowski, Alan P. ; Sun, Haiying ; Brognard, John ; Dennis, Phillip A. / Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt. In: Journal of the American Chemical Society. 2003 ; Vol. 125, No. 5. pp. 1144-1145.
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