Small Molecule Induces Time-Dependent Inhibition of Stat3 Dimerization and DNA-Binding Activity and Regresses Human Breast Tumor Xenografts.

Autor: Yue P; Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA., Chen Y; Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.; Department of Basic Medicine, Suzhou Vocational Health College, Suzhou, 215009, China., Ogese MO; Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA., Sun S; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis, TN, 38163, USA., Zhang X; National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical, Sciences, Sun Yat-Sen University, Guangzhou, 510006, China., Esan T; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064-3095, USA., Buolamwini JK; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis, TN, 38163, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064-3095, USA., Turkson J; Department of Medicine, Division of Hematology-Oncology, Cedars Sinai Medical Center, 8700 Beverly Blvd, Davis 5065, Los Angeles, CA, 90048, USA.; Cancer Biology Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2024 Aug 21, pp. e202400351. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1002/cbic.202400351
Abstrakt: 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 IC 50 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-NH 2 in fluorescent polarization assay with IC 50 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, pErk1/2 MAPK , 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.
(© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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