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Biomolecules 2019, 9(3), 82; https://doi.org/10.3390/biom9030082

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

1
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, Australia
3
Departments of Medicine, Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
Received: 25 January 2019 / Accepted: 21 February 2019 / Published: 26 February 2019
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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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, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ 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. View Full-Text
Keywords: PIK3CA; isoform selectivity; p110; p85; phosphatidylinositol 3-kinase; PI3Kβ; PI3Kα; PI3Kγ; PI3Kδ PIK3CA; isoform selectivity; p110; p85; phosphatidylinositol 3-kinase; PI3Kβ; PI3Kα; PI3Kγ; PI3Kδ
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Miller, M.S.; Thompson, P.E.; Gabelli, S.B. Structural Determinants of Isoform Selectivity in PI3K Inhibitors. Biomolecules 2019, 9, 82.

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