Cargando…
Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms
Class IB phosphoinositide 3-kinase gamma (PI3Kγ) is vital for regulating intracellular signaling pathways and has become an attractive drug target for the treatment of malignant tumors. In the present study, one potent PI3Kγ inhibitor (JN-PK1) with a novel scaffold against hematologic malignancies w...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087882/ https://www.ncbi.nlm.nih.gov/pubmed/35546906 http://dx.doi.org/10.1039/c9ra02649e |
_version_ | 1784704251066318848 |
---|---|
author | Zhu, Jingyu Ke, Ke Xu, Lei Jin, Jian |
author_facet | Zhu, Jingyu Ke, Ke Xu, Lei Jin, Jian |
author_sort | Zhu, Jingyu |
collection | PubMed |
description | Class IB phosphoinositide 3-kinase gamma (PI3Kγ) is vital for regulating intracellular signaling pathways and has become an attractive drug target for the treatment of malignant tumors. In the present study, one potent PI3Kγ inhibitor (JN-PK1) with a novel scaffold against hematologic malignancies was identified based on a series of biological experiments, and then the selective mechanism of PI3Kγ inhibition was explored by a systematic computational method. JN-PK1 shows an effective antiproliferative activity on several cancer cell lines, especially blood cancer cells. Cell-free enzymatic studies demonstrated that JN-PK1 specifically inhibits PI3Kγ at low micromolar concentrations without affecting other isoforms of PI3K. In the cellular context, JN-PK1 potently inhibits PI3K/Akt/mTOR signaling pathway in a time- and concentration-dependent manner, which leads to the apoptosis of cancer cells. Further, the specific binding mode of JN-PK1 with PI3Kγ was illustrated by molecular docking, and the selective inhibition mechanism of PI3Kγ by JN-PK1 was revealed by molecular dynamics simulation. Finally, some key residues of PI3Kγ required for specificity and activity were identified. Taken together, JN-PK1 may be developed as a promising therapeutic agent for the treatment of hematologic malignancies. |
format | Online Article Text |
id | pubmed-9087882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-90878822022-05-10 Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms Zhu, Jingyu Ke, Ke Xu, Lei Jin, Jian RSC Adv Chemistry Class IB phosphoinositide 3-kinase gamma (PI3Kγ) is vital for regulating intracellular signaling pathways and has become an attractive drug target for the treatment of malignant tumors. In the present study, one potent PI3Kγ inhibitor (JN-PK1) with a novel scaffold against hematologic malignancies was identified based on a series of biological experiments, and then the selective mechanism of PI3Kγ inhibition was explored by a systematic computational method. JN-PK1 shows an effective antiproliferative activity on several cancer cell lines, especially blood cancer cells. Cell-free enzymatic studies demonstrated that JN-PK1 specifically inhibits PI3Kγ at low micromolar concentrations without affecting other isoforms of PI3K. In the cellular context, JN-PK1 potently inhibits PI3K/Akt/mTOR signaling pathway in a time- and concentration-dependent manner, which leads to the apoptosis of cancer cells. Further, the specific binding mode of JN-PK1 with PI3Kγ was illustrated by molecular docking, and the selective inhibition mechanism of PI3Kγ by JN-PK1 was revealed by molecular dynamics simulation. Finally, some key residues of PI3Kγ required for specificity and activity were identified. Taken together, JN-PK1 may be developed as a promising therapeutic agent for the treatment of hematologic malignancies. The Royal Society of Chemistry 2019-06-28 /pmc/articles/PMC9087882/ /pubmed/35546906 http://dx.doi.org/10.1039/c9ra02649e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Zhu, Jingyu Ke, Ke Xu, Lei Jin, Jian Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title | Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title_full | Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title_fullStr | Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title_full_unstemmed | Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title_short | Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms |
title_sort | discovery of a novel phosphoinositide 3-kinase gamma (pi3kγ) inhibitor against hematologic malignancies and theoretical studies on its pi3kγ-specific binding mechanisms |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087882/ https://www.ncbi.nlm.nih.gov/pubmed/35546906 http://dx.doi.org/10.1039/c9ra02649e |
work_keys_str_mv | AT zhujingyu discoveryofanovelphosphoinositide3kinasegammapi3kginhibitoragainsthematologicmalignanciesandtheoreticalstudiesonitspi3kgspecificbindingmechanisms AT keke discoveryofanovelphosphoinositide3kinasegammapi3kginhibitoragainsthematologicmalignanciesandtheoreticalstudiesonitspi3kgspecificbindingmechanisms AT xulei discoveryofanovelphosphoinositide3kinasegammapi3kginhibitoragainsthematologicmalignanciesandtheoreticalstudiesonitspi3kgspecificbindingmechanisms AT jinjian discoveryofanovelphosphoinositide3kinasegammapi3kginhibitoragainsthematologicmalignanciesandtheoreticalstudiesonitspi3kgspecificbindingmechanisms |