-
1دورية أكاديمية
المؤلفون: Guillaume Mata (1685596), Dillon H. Miles (8962160), Samuel L. Drew (8682102), Jeremy Fournier (3594275), Kenneth V. Lawson (2391673), Artur K. Mailyan (1588903), Ehesan U. Sharif (6847676), Xuelei Yan (1698157), Joel W. Beatty (1328199), Jesus Banuelos (4036886), Jie Chen (5892), Elaine Ginn (2124058), Ada Chen (1698127), Kimberline Y. Gerrick (6061382), Amber T. Pham (8682105), Kent Wong (2160739), Divyank Soni (9383865), Puja Dhanota (6506090), Stefan G. Shaqfeh (9383868), Cesar Meleza (6899225), Nell Narasappa (11592941), Hema Singh (11592944), Xiaoning Zhao (184301), Lixia Jin (1570120), Ulrike Schindler (9383871), Matthew J. Walters (296691), Stephen W. Young (7022015), Nigel P. Walker (8682108), Manmohan Reddy Leleti (8682111), Jay P. Powers (1721107), Jenna L. Jeffrey (2029015)
مصطلحات موضوعية: Biochemistry, Medicine, Pharmacology, Immunology, Developmental Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, early lead series, tumor immune microenvironment, significant immune response, molecular docking studies, selective pi3kγ inhibitors, pyrazolopyrimidine amide inhibitors, 56 , immune cells, vitro <, studies indicate, pyrazolopyrimidine isoindolinones, optimal amide, metabolic stability, m1 macrophages, like properties, kinase γ, isoindolinone substituents, inflammatory phenotype, inflammatory mediators, increasing pro, highly potent, highly expressed, favorable drug
الوصف: 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.
-
2
المؤلفون: Guillaume Mata (1685596), Dillon H. Miles (8962160), Samuel L. Drew (8682102), Jeremy Fournier (3594275), Kenneth V. Lawson (2391673), Artur K. Mailyan (1588903), Ehesan U. Sharif (6847676), Xuelei Yan (1698157), Joel W. Beatty (1328199), Jesus Banuelos (4036886), Jie Chen (5892), Elaine Ginn (2124058), Ada Chen (1698127), Kimberline Y. Gerrick (6061382), Amber T. Pham (8682105), Kent Wong (2160739), Divyank Soni (9383865), Puja Dhanota (6506090), Stefan G. Shaqfeh (9383868), Cesar Meleza (6899225), Nell Narasappa (11592941), Hema Singh (11592944), Xiaoning Zhao (184301), Lixia Jin (1570120), Ulrike Schindler (9383871), Matthew J. Walters (296691), Stephen W. Young (7022015), Nigel P. Walker (8682108), Manmohan Reddy Leleti (8682111), Jay P. Powers (1721107), Jenna L. Jeffrey (2029015)
مصطلحات موضوعية: Biochemistry, Medicine, Pharmacology, Immunology, Developmental Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, early lead series, tumor immune microenvironment, significant immune response, molecular docking studies, selective pi3kγ inhibitors, pyrazolopyrimidine amide inhibitors, 56 , immune cells, vitro <, studies indicate, pyrazolopyrimidine isoindolinones, optimal amide, metabolic stability, m1 macrophages, like properties, kinase γ, isoindolinone substituents, inflammatory phenotype, inflammatory mediators, increasing pro, highly potent, highly expressed, favorable drug
الوصف: 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.
-
3
المؤلفون: Guillaume Mata (1685596), Dillon H. Miles (8962160), Samuel L. Drew (8682102), Jeremy Fournier (3594275), Kenneth V. Lawson (2391673), Artur K. Mailyan (1588903), Ehesan U. Sharif (6847676), Xuelei Yan (1698157), Joel W. Beatty (1328199), Jesus Banuelos (4036886), Jie Chen (5892), Elaine Ginn (2124058), Ada Chen (1698127), Kimberline Y. Gerrick (6061382), Amber T. Pham (8682105), Kent Wong (2160739), Divyank Soni (9383865), Puja Dhanota (6506090), Stefan G. Shaqfeh (9383868), Cesar Meleza (6899225), Nell Narasappa (11592941), Hema Singh (11592944), Xiaoning Zhao (184301), Lixia Jin (1570120), Ulrike Schindler (9383871), Matthew J. Walters (296691), Stephen W. Young (7022015), Nigel P. Walker (8682108), Manmohan Reddy Leleti (8682111), Jay P. Powers (1721107), Jenna L. Jeffrey (2029015)
مصطلحات موضوعية: Biochemistry, Medicine, Pharmacology, Immunology, Developmental Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, early lead series, tumor immune microenvironment, significant immune response, molecular docking studies, selective pi3kγ inhibitors, pyrazolopyrimidine amide inhibitors, 56 , immune cells, vitro <, studies indicate, pyrazolopyrimidine isoindolinones, optimal amide, metabolic stability, m1 macrophages, like properties, kinase γ, isoindolinone substituents, inflammatory phenotype, inflammatory mediators, increasing pro, highly potent, highly expressed, favorable drug
الوصف: 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.
