Discovery of Potent and Selective PI3Kγ Inhibitors

The selective inhibition of the lipid
signaling enzyme PI3Kγ
constitutes an opportunity to mediate immunosuppression and inflammation
within the tumor microenvironment but is difficult to achieve due
to the high sequence homology across the class I PI3K isoforms. Here,
we describe the design of a novel series of potent PI3Kγ inhibitors
that attain high isoform selectivity through the divergent projection
of substituents into both the “selectivity” and “alkyl-induced”
pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ.
These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)­pyrazolo­[1,5-a]­pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064
μM, THP-1 cells), which displays >600-fold selectivity for
PI3Kγ
over the other class I isoforms and is a promising step toward the
identification of a clinical development candidate. The structure–activity
relationships identified throughout this campaign demonstrate that
greater γ-selectivity can be achieved by inhibitors that occupy
an “alkyl-induced” pocket and possess bicyclic hinge-binding
motifs capable of forming more than one hydrogen bond to the hinge
region of PI3Kγ.