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J Med Chem. 2018 Dec 24. doi: 10.1021/acs.jmedchem.8b01298. [Epub ahead of print]

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.

Author information

1
Respiratory, Inflammation & Autoimmunity Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit , AstraZeneca , Boston , Massachusetts 02451 , United States.
2
Brigham and Women's Hospital , Boston , Massachusetts 02115 , United States.

Abstract

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.

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