From lab to clinic: The discovery and optimization journey of PI3K inhibitors

Lian, Siyu; Du, Zhenhua; Chen, Qingqing; Xia, Yu; Miao, Xinxin; Yu, Weiwei; Sun, Qian; Feng, Chong

doi:10.1016/j.ejmech.2024.116786

European Journal of Medicinal Chemistry

2024

DOI: 10.1016/j.ejmech.2024.116786

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From lab to clinic: The discovery and optimization journey of PI3K inhibitors

Siyu Lian,

Zhenhua Du,

Qingqing Chen

et al.

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In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

Jia,

Liu,

Cheng

et al. 2024

IJMS

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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and it is highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to its lower risk of side effects and personalized medication. Excessive activation of PI3Kδ in DLBCL leads to abnormal activation of the PI3K/Akt pathway, promoting the occurrence and development of DLBCL. The side effects of existing PI3Kδ inhibitors limit their clinical application. The discovery of PI3Kδ inhibitors with novel structures and minimal side effects is urgently needed. This study constructed a PI3Kδ inhibitor screening model to screen natural product libraries. Revealing the mechanism of natural product therapy for DLBCL through network pharmacology, kinase assays, and molecular dynamics. The results of molecular docking indicated that Silibinin had a high docking score and a good binding mode with PI3Kδ. The results of network pharmacology indicated that Silibinin could exert therapeutic effects on DLBCL by inhibiting PI3Kδ activity and affecting the PI3K/Akt pathway. The kinase assays indicated that Silibinin concentration dependently inhibited the activity of PI3Kδ. The results of molecular dynamics indicated that Silibinin could stably bind to PI3Kδ. Silibinin was a structurally novel 3,5,7-trihydroxychroman-4-one PI3Kδ inhibitor, providing valuable information for the subsequent discovery of PI3Kδ inhibitors.

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In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

Jia,

Liu,

Cheng

et al. 2024

IJMS

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show abstract

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From lab to clinic: The discovery and optimization journey of PI3K inhibitors

Cited by 1 publication

References 96 publications

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

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