18 PI3K fragments

As we’ve noted before, kinases are a fertile field for fragment finding, but most of the targets have been protein kinases. Lipid kinases such as the phosphatidylinostide 3-kinases (PI3Ks), which mediate signal transduction by transferring a phosphate group to lipids, are also popular targets for a variety of diseases, but less has been disclosed about their suitability for fragment-based lead discovery. A paper in a recent issue of Bioorg. Med. Chem. Lett. remedies that.

Fabrizio Giordanetto and colleagues at AstraZeneca started with a homology model of p110beta (no crystal structure of this enzyme has been reported). They then used commercial software to dock 183,330 fragments selected from their corporate collection. All fragments that made at least two hydrogen bonds with the protein were organized into clusters of similar molecules and representatives of each cluster were visually inspected. This led to the selection of 210 fragments to be screened against the protein, of which 18 showed measurable activity. Structures of these fragments are provided in the paper; they range from kinase workhorses such as compound 1 to known PI3K motifs such as compound 10 to more unusual molecules such as compound 18. These hits were also tested on other members of the PI3K family, and while most showed activity across the board, others (such as compound 18) showed some selectivity.

There are some interesting structures in here; if I were starting a PI3K program I would definitely take a close look at them. Although the researchers have likely developed some of these into attractive leads, one of the virtues of fragments is that they are often so protean that different teams can start with the same fragment and end up in very different places.