ArticleActa pharmacologica Sinica2016
Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer.
Article in Acta pharmacologica Sinica, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 16 citations in OpenAlex.
- Small-molecule autophagy modulators: Mechanisms, therapeutic potential, and development challenges in pathological settings.Fundamental research · 2026Review
- Identification of potential PIM-2 inhibitors via ligand-based generative models, molecular docking and molecular dynamics simulations.Molecular diversity · 2024Article
- Potential of the enzyme laccase for the synthesis and derivatization of antimicrobial compounds.World journal of microbiology & biotechnology · 2023Review
- PIM1/STAT3 axis: a potential co-targeted therapeutic approach in triple-negative breast cancer.Medical oncology (Northwood, London, England) · 2022Review
- Ring-Closure Mechanisms Mediated by Laccase to Synthesize Phenothiazines, Phenoxazines, and Phenazines.ACS omega · 2020Article
- Targeting autophagy-related protein kinases for potential therapeutic purpose.Acta pharmaceutica Sinica. B · 2020Review
- Negative regulation of AMPKα1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer.Oncogene · 2019Article
- Metal-free formal synthesis of phenoxazine.Beilstein journal of organic chemistry · 2018Article
- Triple negative breast cancer: the kiss of death.Oncotarget · 2017Review
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7 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
aimPim-2 is a short-lived serine/threonine kinase, which plays a key role in metastasis of breast cancer through persistent activation of STAT3. Although the crystal structure of Pim-2 has been reported, but thus far no specific Pim-2-targeted compounds have been reported. In this study, we identified a novel Pim-2 inhibitor, HJ-PI01, by in silico analysis and experimental validation.
methodsThe protein-protein interaction (PPI) network, chemical synthesis, molecular docking, and molecular dynamics (MD) simulations were used to design and discover the new Pim-2 inhibitor HJ-PI01. The anti-tumor effects of HJ-PI01 were evaluated in human breast MDA-MB-231, MDA-MB-468, MDA-MB-436, MCF-7 cells in vitro and in MDA-MB-231 xenograft mice, which were treated with HJ-PI01 (40 mg·kg(-1)·d(-1), ig) with or without lienal polypeptide (50 mg·kg(-1)·d(-1), ip) for 10 d. The apoptosis/autophage-inducing mechanisms of HJ-PI01 were elucidated using Western blots, immunoblots, flow cytometry, transmission electron microscopy and fluorescence microscopy.
resultsBased on the PrePPI network, the potential partners interacting with Pim-2 in regulating apoptosis (160 protein pairs) and autophagy (47 protein pairs) were identified. Based on the structural characteristics of Pim-2, a total of 15 compounds (HJ-PI01 to HJ-P015) were synthesized, which showed moderate or remarkable anti-proliferative potency in the human breast cancer cell lines tested. The most effective compound HJ-PI01 exerted a robust inhibition on MDA-MB-231 cells compared with chlorpromazine and the pan-Pim inhibitor PI003. Molecular dynamics (MD) simulation revealed that HJ-PI01 had a good binding score with Pim-2. Moreover, HJ-PI01 (300 nmol/L) induced death receptor-dependent and mitochondrial apoptosis as well as autophagic death in MDA-MB-231 cells. In MDA-MB-231 xenograft mice, administration of HJ-PI01 remarkably inhibited the tumor growth and induced tumor cell apoptosis in vivo. Co-administration of HJ-PI01 with lienal polypeptide could improve the anti-tumor activity of HJ-PI01 and reduce its toxicity.
conclusionThe newly synthesized compound, HJ-PI01, can induce death receptor/mitochondrial apoptosis and autophagic cell death by targeting Pim-2 in human breast cancer cells in vitro and in vivo.
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