New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kalpha Complexed with a Potent Lead Compound.

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Yang X, Zhang X, Huang M, Song K, Li X, Huang M, Meng L, Zhang J

New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kalpha Complexed with a Potent Lead Compound.

Sci Rep. 2017 Nov 6;7(1):14572. doi: 10.1038/s41598-017-15260-5.

PubMed ID

29109464 [ View in PubMed

]

Abstract

Phosphatidylinositol 3-kinase alpha is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kalpha 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 p110alpha-YXY-4F and apo p110alpha complexes showed that YXY-4F induced additional space by promoting a flexible conformational change in residues Ser773 and Ser774 in the PI3Kalpha ATP catalytic site. Specifically, residue 773(S) in PI3Kalpha is quite different from that of PI3Kbeta (D), gamma (A), and delta (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kalpha.

DrugBank Data that Cites this Article

Drugs

Alpelisib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Alpelisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Protein	Humans	Yes	Inhibitor	Details