6XRN

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

Summary for 6XRN

• Entry DOI: 10.2210/pdb6xrn/pdb
• Related: 6XRL 6XRM
• Descriptor: 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)
• Functional Keywords: phosphoinositide 3-kinase gamma, inhibitor, ab610, immunosuppression, cancer, proteros, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 109206.40

Authors

Walker, N.P.,Jeffrey, J.L. (deposition date: 2020-07-13, release date: 2021-11-03, Last modification date: 2024-05-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.96 Å)