ArticleThe Biochemical journal2012
Definition of the binding mode of a new class of phosphoinositide 3-kinase α-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis.
Article in The Biochemical journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 27 citations in OpenAlex.
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- Structure-based pharmacophore modeling and DFT studies of Indian Ocean-derived red algal compounds as PI3Kα inhibitors.Molecular diversity · 2024Article
- Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.International journal of molecular sciences · 2022Article
- Drug Discovery of Plausible Lead Natural Compounds That Target the Insulin Signaling Pathway: Bioinformatics Approaches.Evidence-based complementary and alternative medicine : eCAM · 2022Review
- PI3K inhibitors: review and new strategies.Chemical science · 2020Review
- Structural Determinants of Isoform Selectivity in PI3K Inhibitors.Biomolecules · 2019Review
- High-throughput screening campaigns against a PI3Kα isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds.Acta pharmacologica Sinica · 2018Article
- New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound.Scientific reports · 2017Article
- Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Definition of the binding mode of phosphoinositide 3-kinase α-selective inhibitor A-66S through molecular dynamics simulation.Journal of molecular modeling · 2014Article
- L-Aminoacyl-triazine derivatives are isoform-selective PI3Kβ inhibitors that target non-conserved Asp862 of PI3KβACS medicinal chemistry letters · 2013Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110α isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non-conserved amino acids in the p110α and p110β isoforms, we have identified three unique binding mechanisms for the p110α-selective inhibitors PIK-75, A-66S and J-32. Each of the inhibitor's p110α-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK-75 interaction bound the non-conserved region 2 amino acid p110α Ser(773), A-66S bound the region 1 non-conserved amino acid p110α Gln(859), and J-32 binding had an indirect interaction with Lys(776) and Ile(771). The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors.
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