2. Academic Validation
  3. A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy

A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy

  • EBioMedicine. 2019 Jun:44:98-111. doi: 10.1016/j.ebiom.2019.05.011.
Zhuan Zhou 1,  Zhiwei Feng 2,  Dong Hu 3,  Peng Yang 2,  Mert Gur 4,  Ivet Bahar 4,  Massimo Cristofanilli 5,  William J Gradishar 5,  Xiang-Qun Xie 6,  Yong Wan 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States.
  • 2 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States.
  • 3 Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States.
  • 4 Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, United States.
  • 5 Lynn Sage Breast Cancer Program, Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States.
  • 6 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States. Electronic address: [email protected].
  • 7 Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Department of Pharmacology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States. Electronic address: [email protected].
PMID: 31101597 DOI: 10.1016/j.ebiom.2019.05.011
Abstract

Background: Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The malignant and invasive feature of TNBCs is correlated with its high Cancer stem cell population. Recent results from us and Others have unveiled an oncogenic role for the PRMT5-KLF4 axis in regulating tumor progression by orchestrating the stemness in mammary tumor cell as well as genome stability. Methylation of KLF4 by PRMT5 leads to KLF4 stabilization, resulting in promoting mitogenesis.

Methods: We have developed a small molecule inhibitor, WX2-43, that specifically intercepts the interaction between PRMT5 and KLF4, thereby enhancing KLF4 degradation.

Findings: Results from our characterization demonstrate that WX2-43 binds to the region between Amino acids L400-M500 on PRMT5. Degradation of KLF4 down-regulates KLF4-mediated genes transcription. We have characterized the potent effect for WX2-43 in inhibiting PRMT5-KLF4 binding that, in turns, suppresses tumor progression and induces tumor cell death in both TNBC cultured-cell and animal models.

Interpretation: WX2-43-mediated inhibition of KLF4 methylation by PRMT5 could be a potential strategy for anti-TNBC treatment. FUND: This work was supported, in whole or in part, by National Institutes of Health grants CA202963 and CA202948 (Wan), R21HL109654 (Xie), P30DA035778 (Xie and Bahar) and P41GM103712 (Bahar).

Keywords

KLF4; Methylation and breast cancer; PRMT5; WX2-43.

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