6XRN

Crystal structure of human PI3K-gamma in complex with Compound 17

6XRN の概要

• エントリーDOI: 10.2210/pdb6xrn/pdb
• 関連するPDBエントリー: 6XRL 6XRM
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(trans-3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (2 entities in total)
• 機能のキーワード: phosphoinositide 3-kinase gamma, inhibitor, ab610, immunosuppression, cancer, proteros, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 109206.40

構造登録者

Walker, N.P.,Jeffrey, J.L. (登録日: 2020-07-13, 公開日: 2021-11-03, 最終更新日: 2024-05-22)

主引用文献

Mata, G.,Miles, D.H.,Drew, S.L.,Fournier, J.,Lawson, K.V.,Mailyan, A.K.,Sharif, E.U.,Yan, X.,Beatty, J.W.,Banuelos, J.,Chen, J.,Ginn, E.,Chen, A.,Gerrick, K.Y.,Pham, A.T.,Wong, K.,Soni, D.,Dhanota, P.,Shaqfeh, S.G.,Meleza, C.,Narasappa, N.,Singh, H.,Zhao, X.,Jin, L.,Schindler, U.,Walters, M.J.,Young, S.W.,Walker, N.P.,Leleti, M.R.,Powers, J.P.,Jeffrey, J.L.
Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase gamma (PI3K gamma ).
J.Med.Chem., 65:1418-1444, 2022

PubMed Abstract: 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 studies indicate that inhibition of PI3Kγ with compound results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.

PubMed: 34672584
DOI: 10.1021/acs.jmedchem.1c01153

実験手法

X-RAY DIFFRACTION (2.96 Å)