Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ).
Guillaume MataDillon H MilesSamuel L DrewJeremy FournierKenneth V LawsonArtur K MailyanEhesan U SharifXuelei YanJoel W BeattyJesus BanuelosJie ChenElaine GinnAda ChenKimberline Y GerrickAmber T PhamKent WongDivyank SoniPuja DhanotaStefan G ShaqfehCesar MelezaNell NarasappaHema SinghXiaoning ZhaoLixia JinUlrike SchindlerMatthew J WaltersStephen W YoungNigel P WalkerManmohan Reddy LeletiJay P PowersJenna L JeffreyPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- structure activity relationship
- molecular docking
- gene expression
- immune response
- molecular dynamics simulations
- case control
- oxidative stress
- protein kinase
- papillary thyroid
- tyrosine kinase
- small molecule
- stem cells
- dna methylation
- high resolution
- squamous cell
- high throughput
- squamous cell carcinoma
- magnetic resonance imaging
- computed tomography
- magnetic resonance
- adverse drug
- mass spectrometry