New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Xiuyan Yang; Xi Zhang; Min Huang; Kun Song; Xuefen Li; Meilan Huang; Linghua  Meng; Jian Zhang

doi:10.1038/s41598-017-15260-5

New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Xiuyan Yang, Xi Zhang, Min Huang, Kun Song, Xuefen Li, Meilan Huang, Linghua Meng, Jian Zhang

School of Chemistry and Chemical Engineering

Research output: Contribution to journal › Article › peer-review

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Abstract

Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a fexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifcally, residue 773(S) in PI3Kα is quite diferent from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.

Original language	English
Article number	14572
Pages (from-to)	1-7
Journal	Scientific Reports
Volume	7
Early online date	06 Nov 2017
DOIs	https://doi.org/10.1038/s41598-017-15260-5
Publication status	Early online date - 06 Nov 2017

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New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound
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Cite this

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title = "New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound",

abstract = "Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a fexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifcally, residue 773(S) in PI3Kα is quite diferent from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.",

author = "Xiuyan Yang and Xi Zhang and Min Huang and Kun Song and Xuefen Li and Meilan Huang and Linghua Meng and Jian Zhang",

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AU - Yang, Xiuyan

AU - Zhang, Xi

AU - Huang, Min

AU - Song, Kun

AU - Li, Xuefen

AU - Huang, Meilan

AU - Meng, Linghua

AU - Zhang, Jian

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N2 - Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a fexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifcally, residue 773(S) in PI3Kα is quite diferent from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.

AB - Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a fexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifcally, residue 773(S) in PI3Kα is quite diferent from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα.

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DO - 10.1038/s41598-017-15260-5

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SN - 2045-2322

M1 - 14572

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New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Abstract

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