A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia

• Published in: PloS one 2022-11, Vol.17 (11), p.e0277893-e0277893
• Main Authors: Chen, Yi, Wu, Tianze, Yang, Chengbin, Lu, Mingzhu, Chen, Zhenxia, Deng, Mingli, Jia, Yu, Yang, Yongtai, Liu, Xiaofeng, Wang, Hongyan, Ling, Yun, Lu, Lei, Zhou, Yaming
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute myeloid leukemia; AKT protein; Apoptosis; Bioinformatics; Biology and Life Sciences; Caspase-3; Cell cycle; Cell growth; Cell Proliferation; Cell survival; Computer and Information Sciences; Conjugation; Engineering and Technology; Enzymatic activity; Enzyme activity; Enzymes; Health aspects; Humans; Inhibitors; Kinases; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Malignancy; Mcl-1 protein; Medicine and Health Sciences; Optimization; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyridine; Research and analysis methods; Signal transduction; Signaling; Sulfonamides; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcriptomes; White people
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0277893

Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.