Phosphoinositide 3-kinase α inhibitors: a patent review

The alpha isoform of the class 1A family of phosphatidylinositol 3-kinases (PI3Kα) has been extensively studied and exploited as a target for cancer drugs. A large number of compounds, from a wide variety of structural scaffolds, are in development. There is an ongoing debate about the desirability for selectivity between PI3Kα and the other isoforms.

The article briefly outlines the nature and role of the class 1A PI3K in cell signalling and provides a table of representative inhibitors of these enzymes that have proceeded to clinical trial, with literature data on their isoform selectivity. It covers the published patent literature from 2011 to 2012 (search completed in December 2012), with a particular focus on compounds with a level of selective inhibition of PI3Kα. In most cases, representative examples of claimed compounds and data on their inhibitory effects are provided.

Features of the development of PI3K inhibitors to date have been the plasticity of the enzymes, which possess binding sites for a bewildering number of small molecule scaffolds, and the need to determine the optimal patterns of selectivity between both the PI3K isoforms and the related downstream serine/threonine kinase mammalian target of rapamycin (mTOR) for therapeutic effect. Both themes are apparent in the recent patents reviewed here, with a wide variety of drug types, including variations on existing scaffolds and completely new ones, being evident. While many of these are dual PI3K/mTOR inhibitors, the PI3Kα-selective pyrido[2,3-b]pyrazine heterocycles reported by Intellikine and the (thiazolyl)pyrrolidinecarboxamides of Novartis are of particular interest.