Isoenzyme Selective Phosphoinositide 3-Kinase Inhibition: What do the Stones Kill?

Laszlo      Buday; Szabolcs      Sipeki

doi:10.2174/157436211797484001

Abstract

Signalling from receptor tyrosine kinases is presumably the most investigated pathway so far and myriad of protein components and respective interactions involved have been outlined. Considerably, disconcerted receptor tyrosine kinase signalling has been implicated in the generation and maintenance of many different human diseases. The two crucial interlinked axes in receptor tyrosine kinase signalling have received immense attention as therapeutic targets. One contains the Ras activated Raf kinases and their object kinase cascade, the other involves phosphoinositide 3-kinase (PI3K) and downstream targets like the protein kinase Akt (also known as protein kinase B). The PI3K pathway regulates various cellular functions such as proliferation, survival, migration and metabolism. Small molecule PI3K inhibitors with isoenzyme selectivity have been developed in growing number and used as tools to elucidate the isoenzyme specific functions. The pharmacological inhibitors assayed for potentials as therapeutic agents in the treatment of diseases as diverse as cancer, leukaemia, thrombosis and allergic response in different model systems presented promising and also some unexpected results.

Keywords: phosphoinositide 3-Kinase, isoenzyme, selective, inhibition, receptor tyrosine kinases, insulin signalling, cancer, thrombosis, leukaemia, p110 alpha, p110 beta, p110 gamma, p110 delta, G-protein coupled receptors, Ras, c-Met, PKB/Akt, PTEN, Glycoprotein VI, B cells, AML, ERBB2, cell cycle, embryonic development, mutation