posted on 2021-10-21, 19:07authored byGuillaume Mata, Dillon H. Miles, Samuel L. Drew, Jeremy Fournier, Kenneth V. Lawson, Artur K. Mailyan, Ehesan U. Sharif, Xuelei Yan, Joel W. Beatty, Jesus Banuelos, Jie Chen, Elaine Ginn, Ada Chen, Kimberline Y. Gerrick, Amber T. Pham, Kent Wong, Divyank Soni, Puja Dhanota, Stefan G. Shaqfeh, Cesar Meleza, Nell Narasappa, Hema Singh, Xiaoning Zhao, Lixia Jin, Ulrike Schindler, Matthew J. Walters, Stephen W. Young, Nigel P. Walker, Manmohan Reddy Leleti, Jay P. Powers, Jenna L. Jeffrey
Phosphoinositide-3-kinase γ
(PI3Kγ) is highly expressed
in immune cells and promotes the production and migration of inflammatory
mediators. The inhibition of PI3Kγ has been shown to repolarize
the tumor immune microenvironment to a more inflammatory phenotype,
thereby controlling immune suppression in cancer. Herein, we report
the structure-based optimization of an early lead series of pyrazolopyrimidine
isoindolinones, which culminated in the discovery of highly potent
and isoform-selective PI3Kγ inhibitors with favorable drug-like
properties. X-ray cocrystal structure analysis, molecular docking
studies, and detailed structure–activity relationship investigations
resulted in the identification of the optimal amide and isoindolinone
substituents to achieve a desirable combination of potency, selectivity,
and metabolic stability. Preliminary in vitro studies
indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory
cytokine gene expression in M1 macrophages.