Discovery and Characterization of a Potent and Selective Inhibitor for Human Phosphoinositide‐3‐kinase γ

Abstract

Phosphoinositide‐3‐kinases (PI3K) belong to the class 1 family of signal transducing enzymes comprised of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Together they are part of the PI3K‐Akt pathway acting as secondary messengers by catalyzing the phosphorylation of the inositol ring of phosphoinositides to regulate key cell functions such as proliferation, differentiation, and migration.Of the four isoforms, PI3Kγ has garnered attention for its expression on immune cells and its role in tumor progression, inflammation, and immune response. PI3Kγ activity has been correlated to cell proliferation and tumor growth in human pancreatic ductal adenocarcinoma (PDAC) and in hepato cellular carcinoma (HCC). Additionally, PI3Kγ inhibition is suggested to be a key switch within the tumor microenvironment between immune stimulation and suppression. This suggest that selective inhibition of PI3Kγ may be an effective anti‐cancer strategy.Previous attempts to selectively target PI3Kγ have proven largely unfruitful due to the poor selectivity profiles of many of the available inhibitors. We have developed a potent, reversible and selective small molecule PI3Kγ inhibitor. This inhibitor (compound 1) demonstrates activity against recombinant human PI3Kγ with sub nanomolar potency as determined by detection of ADP generation measured by luminescence. Additionally, compound 1 is highly selective over the rest of the class 1 PI3K family. Finally, compound 1 shows double digit nanomolar potency in MCP‐1 induced THP cells as measured by phosphorylation of AKT Ser473 using AlphaLisa and low triple digit nanomolar potency in whole blood as measured by flow cytometry.