Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Biomolecules
Michelle S MillerSandra B Gabelli

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

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Citations

May 9, 2019·Pharmaceuticals·Daniel A RodriguesCarlos A M Fraga
Sep 5, 2019·Biomolecules·Bernd Nürnberg, Sandra Beer-Hammer
Apr 16, 2020·Expert Opinion on Pharmacotherapy·Anna Maria FrustaciMarco Montillo
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Mar 19, 2020·ACS Medicinal Chemistry Letters·Gaye WhiteCharles A Brearley
Sep 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xinran LiLydia W T Cheung
Nov 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xiao LiuPeter K Vogt
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Jan 5, 2022·Biomedical Chromatography : BMC·Dipali SonawanePinaki Sengupta

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Methods Mentioned

BETA
X-ray

Software Mentioned

WaterMap

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