ArticleNature chemical biology2019
A class of highly selective inhibitors bind to an active state of PI3Kγ.
Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed.
- PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.Nature communications · 2026Article
- Engineering selective PI3KActa pharmaceutica Sinica. B · 2026Article
- Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression.Cell reports. Medicine · 2026Article
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Article
- ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.The Biochemical journal · 2024Article
- Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.Molecular cancer · 2024Review
- Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ.Nature structural & molecular biology · 2024Article
- Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.Nature cancer · 2024Article
- Development of PI3Kγ selective inhibitors: the strategies and application.Acta pharmacologica Sinica · 2024Review
- Article
- Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.bioRxiv : the preprint server for biology · 2023Article
- Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs.Cell reports · 2023Article
- The role of PI3Kγ in the immune system: new insights and translational implications.Nature reviews. Immunology · 2022Review
- 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
- Kinases on Double Duty: A Review of UniProtKB Annotated Bifunctionality within the Kinome.Biomolecules · 2022Review
- QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods.Scientific reports · 2022Article
- PI3K inhibitors are finally coming of age.Nature reviews. Drug discovery · 2021Review
- Article
- Mechanism of auto-inhibition and activation of Mec1Nature structural & molecular biology · 2021Article
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
We have discovered a class of PI3Kγ inhibitors exhibiting over 1,000-fold selectivity over PI3Kα and PI3Kβ. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kγ. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kγ, which is unique to these compounds and to the PI3Kγ isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors.
Indexed as
Identifiers
30718815What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.