Fragments vs PI3K – AstraZeneca’s turn

Last year we highlighted a paper from AstraZeneca in which they used virtual screening to identify fragments that inhibit the p110β isoform of phosphoinositide 3-kinase (PI3K), a potential anti-cancer and antithrombotic target. In two recent papers in Bioorg. Med. Chem. Lett., Fabrizio Giordanetto and colleagues describe the optimization of one of these fragments to a potent, selective molecule with in vivo efficacy.

The first paper describes the initial fragment-to-lead work. A variety of changes to fragment 1 were explored, including adding a lipophilic phenyl group to increase potency (compound 2). At the same time, modifications were explored in the central pyrimidinone ring. Although compound 3 was less active than compound 2, it also had a considerably lower logD. Many additional changes were explored, and ultimately one of the most potent compounds was compound 16. The isomeric compound 22 was less potent, but had significantly better solublility and stability in a microsomal assay.

The second paper describes subsequent optimization, ultimately yielding compound (S)-21. There’s a lot of good medicinal chemistry that I can’t do justice to here, so definitely check out the two papers themselves. Compound (S)-21 is potent, selective against the related kinase p110α, and shows good activity in a dog model of platelet aggregation without causing an increase in bleeding time.

One of the nice things about this work is the fact that the researchers used a fragment-hopping approach and were not focused on potency to the exclusion of all other properties. Although one could argue that this is simply good medicinal chemistry, it can sometimes fall into the category of what Mike Hann has memorably christened “unknown knowns,” a trap this team avoided.