作者
Guillaume Mata,Dillon H. Miles,Samuel L. Drew,J. Fournier,Kenneth V. Lawson,Artur K. Mailyan,Ehesan U. Sharif,Xuelei Yan,Joel W. Beatty,Jésus Banuelos,Jie Chen,Elaine Ginn,Ada Chen,Kimberline Y Gerrick,Amber 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 Walker,Manmohan R. Leleti,Jay P. Powers,Jenna L. Jeffrey
摘要
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.