Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt.
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.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tumor Cells, Cultured
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins
- Protein Serine-Threonine Kinases
- Phosphorylation
- Phosphatidylinositols
- Lung Neoplasms
- Humans
- General Chemistry
- Enzyme Inhibitors
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tumor Cells, Cultured
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins
- Protein Serine-Threonine Kinases
- Phosphorylation
- Phosphatidylinositols
- Lung Neoplasms
- Humans
- General Chemistry
- Enzyme Inhibitors