Related Experiment Video
Updated: Jun 15, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Small Molecule Induces Time-Dependent Inhibition of Stat3 Dimerization and DNA-Binding Activity and Regresses Human
Peibin Yue1,2, Yue Chen1,2,3, Monday O Ogese1,2
1Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.
Abstract:
Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 μM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 μM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, and Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1, pErk1/2MAPK, pShc, pJAK2, or pSrc induction, or on cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.
Insights
A new drug, JKB887, effectively inhibits Signal Transducer and Activator of Transcription 3 (Stat3) by targeting its SH2 domain. This Stat3 inhibitor demonstrates significant antitumor effects in preclinical models of human cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrantly active Signal Transducer and Activator of Transcription 3 (Stat3) is implicated in numerous human cancers.
- Stat3 is a validated anticancer target but presents challenges for drug development.
Purpose of the Study:
- To identify and characterize a novel small molecule inhibitor of Stat3.
- To evaluate the anticancer efficacy of the identified inhibitor, JKB887, in preclinical models.
Main Methods:
- Library screening to identify JKB887, a small molecule predicted to bind the Stat3 SH2 domain.
- In vitro assays to assess JKB887's inhibition of Stat3 DNA-binding and peptide binding.
- In vitro and in vivo studies to evaluate JKB887's effects on Stat3 signaling, gene expression, and tumor growth in cancer cells and xenografts.
Main Results:
- JKB887 inhibited Stat3 DNA-binding activity in vitro with IC50 values of 2.2-4.5 μM.
- JKB887 directly disrupted Stat3 binding to a pTyr peptide and inhibited Stat3 phosphorylation, nuclear translocation, and transcriptional activity in cancer cells.
- JKB887 demonstrated selectivity for Stat3, with minimal effects on other signaling pathways, and inhibited human breast cancer xenograft growth in mice.
Conclusions:
- JKB887 is a novel, Stat3-selective inhibitor with potent anticancer activity.
- JKB887 shows promise as a therapeutic agent for Stat3-dependent human cancers.
More Related Videos
11:13Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
08:48An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
