Mechanisms of PI3Kβ-selective inhibition revealed by reciprocal mutagenesis.

Abstract

The p110β isoform of PI3 kinase (PI3Kβ) has been implicated in pathological disorders such as thrombosis and cancer and a number of PI3Kβ-selective inhibitors have recently progressed into clinical studies. Although crystallography studies identify a binding site conformation favored by the inhibitors, no specific interaction explains the observed selectivity. Using site-directed mutagenesis we have identified a specific tyrosine residue of the binding site Y778 that dictates the ability of the PI3Kβ isoform to bind these inhibitors. When mutated to isoleucine, PI3Kβ has reduced ability to present a specific cryptic binding site into which a range of reported PI3Kβ inhibitors can bind, and conversely when tyrosine is introduced into the same position in PI3Kα, the same inhibitors gain potency. The results provide a cogent explanation for the selectivity profiles displayed by these PI3K inhibitors and maybe others as well.

• Authors: Zhaohua Zheng, Michelle S Miller, Ian G Jennings, Philip E Thompson
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 8 Issue 4 Pg. 679-83 (Apr 19 2013) ISSN: 1554-8937 [Electronic] United States
• PMID: 23360067 (Publication Type: Letter, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Isoenzymes
• Phosphoinositide-3 Kinase Inhibitors

Topics

• Enzyme Inhibitors (pharmacology)
• Isoenzymes (antagonists & inhibitors, chemistry)
• Models, Molecular
• Mutagenesis
• Phosphatidylinositol 3-Kinases (chemistry)
• Phosphoinositide-3 Kinase Inhibitors