Structural Determinants of Isoform Selectivity in PI3K Inhibitors
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 physiologi...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-02-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/9/3/82 |
| _version_ | 1818430792441790464 |
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| author | Michelle S. Miller Philip E. Thompson Sandra B. Gabelli |
| author_facet | Michelle S. Miller Philip E. Thompson Sandra B. Gabelli |
| author_sort | Michelle S. Miller |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T15:39:02Z |
| format | Article |
| id | doaj.art-5aefe6381968449882fd1fadb8c4cc1b |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-14T15:39:02Z |
| publishDate | 2019-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-5aefe6381968449882fd1fadb8c4cc1b2022-12-21T22:55:39ZengMDPI AGBiomolecules2218-273X2019-02-01938210.3390/biom9030082biom9030082Structural Determinants of Isoform Selectivity in PI3K InhibitorsMichelle S. Miller0Philip E. Thompson1Sandra B. Gabelli2Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, AustraliaDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAPhosphatidylinositol 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.https://www.mdpi.com/2218-273X/9/3/82PIK3CAisoform selectivityp110p85phosphatidylinositol 3-kinasePI3KβPI3KαPI3KγPI3Kδ |
| spellingShingle | Michelle S. Miller Philip E. Thompson Sandra B. Gabelli Structural Determinants of Isoform Selectivity in PI3K Inhibitors Biomolecules PIK3CA isoform selectivity p110 p85 phosphatidylinositol 3-kinase PI3Kβ PI3Kα PI3Kγ PI3Kδ |
| title | Structural Determinants of Isoform Selectivity in PI3K Inhibitors |
| title_full | Structural Determinants of Isoform Selectivity in PI3K Inhibitors |
| title_fullStr | Structural Determinants of Isoform Selectivity in PI3K Inhibitors |
| title_full_unstemmed | Structural Determinants of Isoform Selectivity in PI3K Inhibitors |
| title_short | Structural Determinants of Isoform Selectivity in PI3K Inhibitors |
| title_sort | structural determinants of isoform selectivity in pi3k inhibitors |
| topic | PIK3CA isoform selectivity p110 p85 phosphatidylinositol 3-kinase PI3Kβ PI3Kα PI3Kγ PI3Kδ |
| url | https://www.mdpi.com/2218-273X/9/3/82 |
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